Design, synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues - Bodapati, Krishna Chaitanya; Soudy, Rania; Etayash, Hashem; Stiles, Michael; Kaur, Kamaljit (Bioorganic & Medicinal Chemistry, 2013)

Design, synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues - Bodapati, Krishna Chaitanya; Soudy, Rania; Etayash, Hashem; Stiles, Michael; Kaur, Kamaljit (Bioorganic & Medicinal Chemistry, 2013)

Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides - Thongyoo, Panumart; Roqué-Rosell, Núria; Leatherbarrow, Robin J.; Tate, Edward W. (Organic & Biomolecular Chemistry, 2008)

Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides - Thongyoo, Panumart; Roqué-Rosell, Núria; Leatherbarrow, Robin J.; Tate, Edward W. (Organic & Biomolecular Chemistry, 2008)

Synthesis by native chemical ligation and characterization of the scorpion toxin AmmTx3 - Zoukimian, Claude; Meudal, Hervé; De Waard, Stephan; Ouares, Karima Ait; Nicolas, Sébastien; Canepari, Marco; Béroud, Rémy; Landon, Céline; De Waard, Michel; Boturyn, Didier (Bioorganic & Medicinal Chemistry, 2019)

Synthesis by native chemical ligation and characterization of the scorpion toxin AmmTx3 - Zoukimian, Claude; Meudal, Hervé; De Waard, Stephan; Ouares, Karima Ait; Nicolas, Sébastien; Canepari, Marco; Béroud, Rémy; Landon, Céline; De Waard, Michel; Boturyn, Didier (Bioorganic & Medicinal Chemistry, 2019)

Incorporation of Selenomethionine into Proteins through Selenohomocysteine-Mediated Ligation - Roelfes, Gerard; Hilvert, Donald (Angewandte Chemie International Edition, 2003)

Incorporation of Selenomethionine into Proteins through Selenohomocysteine-Mediated Ligation - Roelfes, Gerard; Hilvert, Donald (Angewandte Chemie International Edition, 2003)

Synthesis of a Dicarba Analogue of Human β-Defensin-1 Using a Combined Ring Closing Metathesis–Native Chemical Ligation Strategy - Heapy, Amanda M.; Williams, Geoffrey M.; Fraser, John D.; Brimble, Margaret A. (Organic Letters, 2012)

Synthesis of a Dicarba Analogue of Human β-Defensin-1 Using a Combined Ring Closing Metathesis–Native Chemical Ligation Strategy - Heapy, Amanda M.; Williams, Geoffrey M.; Fraser, John D.; Brimble, Margaret A. (Organic Letters, 2012)

Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging - Honarvar, Hadis; Jokilaakso, Nima; Andersson, Karl; Malmberg, Jennie; Rosik, Daniel; Orlova, Anna; Karlström, Amelie Eriksson; Tolmachev, Vladimir; Järver, Peter (Nuclear Medicine and Biology, 2013)

Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging - Honarvar, Hadis; Jokilaakso, Nima; Andersson, Karl; Malmberg, Jennie; Rosik, Daniel; Orlova, Anna; Karlström, Amelie Eriksson; Tolmachev, Vladimir; Järver, Peter (Nuclear Medicine and Biology, 2013)

Thiazolidine-Protected β-Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry - Sayers, Jessica; Thompson, Robert E.; Perry, Kristen J.; Malins, Lara R.; Payne, Richard J. (Organic Letters, 2015)

Thiazolidine-Protected β-Thiol Asparagine: Applications in One-Pot Ligation–Desulfurization Chemistry - Sayers, Jessica; Thompson, Robert E.; Perry, Kristen J.; Malins, Lara R.; Payne, Richard J. (Organic Letters, 2015)

Synthesis of Chlorotoxin by Native Chemical Ligation - Karaca, Ulvi; Kesici, Seçkin; Özçubukçu, Salih (Journal of the Turkish Chemical Society, Section A: Chemistry, 2018)

Synthesis of Chlorotoxin by Native Chemical Ligation - Karaca, Ulvi; Kesici, Seçkin; Özçubukçu, Salih (Journal of the Turkish Chemical Society, Section A: Chemistry, 2018)

N -Sulfanylethylaminooxybutyramide (SEAoxy): A Crypto-Thioester Compatible with Fmoc Solid-Phase Peptide Synthesis - Tsuda, Shugo; Mochizuki, Masayoshi; Sakamoto, Ken; Denda, Masaya; Nishio, Hideki; Otaka, Akira; Yoshiya, Taku (Organic Letters, 2016)

N -Sulfanylethylaminooxybutyramide (SEAoxy): A Crypto-Thioester Compatible with Fmoc Solid-Phase Peptide Synthesis - Tsuda, Shugo; Mochizuki, Masayoshi; Sakamoto, Ken; Denda, Masaya; Nishio, Hideki; Otaka, Akira; Yoshiya, Taku (Organic Letters, 2016)

Native Chemical Ligation at Asx-Cys, Glx-Cys: Chemical Synthesis and High-Resolution X-ray Structure of ShK Toxin by Racemic Protein Crystallography - Dang, Bobo; Kubota, Tomoya; Mandal, Kalyaneswar; Bezanilla, Francisco; Kent, Stephen B. H. (Journal of the American Chemical Society, 2013)

Native Chemical Ligation at Asx-Cys, Glx-Cys: Chemical Synthesis and High-Resolution X-ray Structure of ShK Toxin by Racemic Protein Crystallography - Dang, Bobo; Kubota, Tomoya; Mandal, Kalyaneswar; Bezanilla, Francisco; Kent, Stephen B. H. (Journal of the American Chemical Society, 2013)

Facile synthesis of C-terminal peptide hydrazide and thioester of NY-ESO-1 (A39-A68) from an Fmoc-hydrazine 2-chlorotrityl chloride resin - Huang, Yi-Chao; Chen, Chen-Chen; Li, Si-Jian; Gao, Shuai; Shi, Jing; Li, Yi-Ming (Tetrahedron, 2014)

Facile synthesis of C-terminal peptide hydrazide and thioester of NY-ESO-1 (A39-A68) from an Fmoc-hydrazine 2-chlorotrityl chloride resin - Huang, Yi-Chao; Chen, Chen-Chen; Li, Si-Jian; Gao, Shuai; Shi, Jing; Li, Yi-Ming (Tetrahedron, 2014)

An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS - Park, Sungkyu; Gunasekera, Sunithi; Aboye, Teshome Leta; Göransson, Ulf (International Journal of Peptide Research and Therapeutics, 2010)

An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS - Park, Sungkyu; Gunasekera, Sunithi; Aboye, Teshome Leta; Göransson, Ulf (International Journal of Peptide Research and Therapeutics, 2010)

The Effect of Backbone Cyclization on the Thermodynamics of β -Sheet Unfolding: Stability Optimization of the PIN WW Domain - Deechongkit, Songpon; Kelly, Jeffery W. (Journal of the American Chemical Society, 2002)

The Effect of Backbone Cyclization on the Thermodynamics of β -Sheet Unfolding: Stability Optimization of the PIN WW Domain - Deechongkit, Songpon; Kelly, Jeffery W. (Journal of the American Chemical Society, 2002)

Synthesis of Cyclic Peptides and Cyclic Proteins via Ligation of Peptide Hydrazides - Zheng, Ji-Shen; Tang, Shan; Guo, Ye; Chang, Hao-Nan; Liu, Lei (ChemBioChem, 2012)

Synthesis of Cyclic Peptides and Cyclic Proteins via Ligation of Peptide Hydrazides - Zheng, Ji-Shen; Tang, Shan; Guo, Ye; Chang, Hao-Nan; Liu, Lei (ChemBioChem, 2012)

Chemical Protein Synthesis Using a Second-Generation N -Acylurea Linker for the Preparation of Peptide-Thioester Precursors - Blanco-Canosa, Juan B.; Nardone, Brunello; Albericio, Fernando; Dawson, Philip E. (Journal of the American Chemical Society, 2015)

Chemical Protein Synthesis Using a Second-Generation N -Acylurea Linker for the Preparation of Peptide-Thioester Precursors - Blanco-Canosa, Juan B.; Nardone, Brunello; Albericio, Fernando; Dawson, Philip E. (Journal of the American Chemical Society, 2015)

Total synthesis of the macrocyclic cysteine knot microprotein MCoTI-II - Thongyoo, Panumart; Tate, Edward W.; Leatherbarrow, Robin J. (Chemical Communications, 2006)

Total synthesis of the macrocyclic cysteine knot microprotein MCoTI-II - Thongyoo, Panumart; Tate, Edward W.; Leatherbarrow, Robin J. (Chemical Communications, 2006)

Synthesis of an O -acyl isopeptide by using native chemical ligation in an aqueous solvent system: SYNTHESIS OF O -ACYL ISOPEPTIDE BY NATIVE CHEMICAL LIGATION - Kawashima, Hiroyuki; Kuruma, Tomomi; Yamashita, Masayuki; Sohma, Youhei; Akaji, Kenichi (Journal of Peptide Science, 2014)

Synthesis of an O -acyl isopeptide by using native chemical ligation in an aqueous solvent system: SYNTHESIS OF O -ACYL ISOPEPTIDE BY NATIVE CHEMICAL LIGATION - Kawashima, Hiroyuki; Kuruma, Tomomi; Yamashita, Masayuki; Sohma, Youhei; Akaji, Kenichi (Journal of Peptide Science, 2014)

One-Pot Peptide Ligation–Desulfurization at Glutamate - Cergol, Katie M.; Thompson, Robert E.; Malins, Lara R.; Turner, Peter; Payne, Richard J. (Organic Letters, 2014)

One-Pot Peptide Ligation–Desulfurization at Glutamate - Cergol, Katie M.; Thompson, Robert E.; Malins, Lara R.; Turner, Peter; Payne, Richard J. (Organic Letters, 2014)

Semisynthesis of Peptoid–Protein Hybrids by Chemical Ligation at Serine - Levine, Paul M.; Craven, Timothy W.; Bonneau, Richard; Kirshenbaum, Kent (Organic Letters, 2014)

Semisynthesis of Peptoid–Protein Hybrids by Chemical Ligation at Serine - Levine, Paul M.; Craven, Timothy W.; Bonneau, Richard; Kirshenbaum, Kent (Organic Letters, 2014)

Racemic crystal structures of peptide toxins, GsMTx4 prepared by protein total synthesis - Qu, Qian; Gao, Shuai; Li, Yi-Ming (Journal of Peptide Science, 2018)

Racemic crystal structures of peptide toxins, GsMTx4 prepared by protein total synthesis - Qu, Qian; Gao, Shuai; Li, Yi-Ming (Journal of Peptide Science, 2018)

Towards biomolecular assembly employing extended native chemical ligation in combination with thioester synthesis using an N→S acyl shift - Ackrill, Tom; Anderson, David W.; Macmillan, Derek (Biopolymers, 2010)

Towards biomolecular assembly employing extended native chemical ligation in combination with thioester synthesis using an N→S acyl shift - Ackrill, Tom; Anderson, David W.; Macmillan, Derek (Biopolymers, 2010)

Thia Zip Reaction for Synthesis of Large Cyclic Peptides: Mechanisms and Applications † - Tam, James P.; Lu, Yi-An; Yu, Qitao (Journal of the American Chemical Society, 1999)

Thia Zip Reaction for Synthesis of Large Cyclic Peptides: Mechanisms and Applications † - Tam, James P.; Lu, Yi-An; Yu, Qitao (Journal of the American Chemical Society, 1999)

t-boc synthesis of huwentoxin-i through native chemical ligation incorporating a trifluoromethanesulfonic acid cleavage strategy: t-Boc Synthesis of Huwentoxin-I - Thapa, Parashar; Cabalteja, Chino C.; Philips, Edwin E.; Espiritu, Michael J.; Peigneur, Steve; Mille, Bea G.; Tytgat, Jan; Cummins, Theodore R.; Bingham, Jon-Paul (Biopolymers, 2016)

t-boc synthesis of huwentoxin-i through native chemical ligation incorporating a trifluoromethanesulfonic acid cleavage strategy: t-Boc Synthesis of Huwentoxin-I - Thapa, Parashar; Cabalteja, Chino C.; Philips, Edwin E.; Espiritu, Michael J.; Peigneur, Steve; Mille, Bea G.; Tytgat, Jan; Cummins, Theodore R.; Bingham, Jon-Paul (Biopolymers, 2016)

Development of a sufficiently reactive thioalkylester involving the side-chain thiol of cysteine applicable for kinetically controlled ligation: Development of a Sufficiently Reactive Thioalkylester - Tsuda, Shugo; Mochizuki, Masayoshi; Nishio, Hideki; Yoshiya, Taku; Nishiuchi, Yuji (Biopolymers, 2016)

Development of a sufficiently reactive thioalkylester involving the side-chain thiol of cysteine applicable for kinetically controlled ligation: Development of a Sufficiently Reactive Thioalkylester - Tsuda, Shugo; Mochizuki, Masayoshi; Nishio, Hideki; Yoshiya, Taku; Nishiuchi, Yuji (Biopolymers, 2016)

The Mercaptomethyl Group Facilitates an Efficient One-Pot Ligation at Xaa-Ser/Thr for (Glyco)peptide Synthesis - Hojo, Hironobu; Ozawa, Chinatsu; Katayama, Hidekazu; Ueki, Akiharu; Nakahara, Yuko; Nakahara, Yoshiaki (Angewandte Chemie, 2010)

The Mercaptomethyl Group Facilitates an Efficient One-Pot Ligation at Xaa-Ser/Thr for (Glyco)peptide Synthesis - Hojo, Hironobu; Ozawa, Chinatsu; Katayama, Hidekazu; Ueki, Akiharu; Nakahara, Yuko; Nakahara, Yoshiaki (Angewandte Chemie, 2010)

Peptidyl N-alkylcysteine as a peptide thioester surrogate in the native chemical ligation - Asahina, Yuya; Nabeshima, Kei; Hojo, Hironobu (Tetrahedron Letters, 2015)

Peptidyl N-alkylcysteine as a peptide thioester surrogate in the native chemical ligation - Asahina, Yuya; Nabeshima, Kei; Hojo, Hironobu (Tetrahedron Letters, 2015)

Peptide Self-Replication Via Template-Directed Ligation - Severin, Kay; Lee, David H.; Martinez, Jose A.; Ghadiri, M. Reza (Chemistry - A European Journal, 1997)

Peptide Self-Replication Via Template-Directed Ligation - Severin, Kay; Lee, David H.; Martinez, Jose A.; Ghadiri, M. Reza (Chemistry - A European Journal, 1997)

Photolabile Protection for One-Pot Sequential Native Chemical Ligation - Ueda, Satoshi; Fujita, Mizuno; Tamamura, Hirokazu; Fujii, Nobutaka; Otaka, Akira (ChemBioChem, 2005)

Photolabile Protection for One-Pot Sequential Native Chemical Ligation - Ueda, Satoshi; Fujita, Mizuno; Tamamura, Hirokazu; Fujii, Nobutaka; Otaka, Akira (ChemBioChem, 2005)

A novel neoglycopeptide linkage compatible with native chemical ligation - Macmillan, Derek; Blanc, Javier (Organic & Biomolecular Chemistry, 2006)

A novel neoglycopeptide linkage compatible with native chemical ligation - Macmillan, Derek; Blanc, Javier (Organic & Biomolecular Chemistry, 2006)

Cysteine-Derived S -Protected Oxazolidinones: Potential Chemical Devices for the Preparation of Peptide Thioesters - Ohta, Yusuke; Itoh, Saori; Shigenaga, Akira; Shintaku, Saori; Fujii, Nobutaka; Otaka, Akira (Organic Letters, 2006)

Cysteine-Derived S -Protected Oxazolidinones: Potential Chemical Devices for the Preparation of Peptide Thioesters - Ohta, Yusuke; Itoh, Saori; Shigenaga, Akira; Shintaku, Saori; Fujii, Nobutaka; Otaka, Akira (Organic Letters, 2006)

Synthesis of Nesiritide via Ligation of Peptide Hydrazide - Chen, Chenchen; Li, Sijian; Chen, Yiqun; Xu, Huajian; Li, Yiming (Chinese Journal of Organic Chemistry, 2014)

Synthesis of Nesiritide via Ligation of Peptide Hydrazide - Chen, Chenchen; Li, Sijian; Chen, Yiqun; Xu, Huajian; Li, Yiming (Chinese Journal of Organic Chemistry, 2014)

A novel ring opening reaction of peptide N-terminal thiazolidine with 2,2′-dipyridyl disulfide (DPDS) efficient for protein chemical synthesis - Katayama, Hidekazu; Morisue, Satoki (Tetrahedron, 2017)

A novel ring opening reaction of peptide N-terminal thiazolidine with 2,2′-dipyridyl disulfide (DPDS) efficient for protein chemical synthesis - Katayama, Hidekazu; Morisue, Satoki (Tetrahedron, 2017)

Backbone Cyclization and Dimerization of LL-37-Derived Peptides Enhance Antimicrobial Activity and Proteolytic Stability - Gunasekera, Sunithi; Muhammad, Taj; Strömstedt, Adam A.; Rosengren, K. Johan; Göransson, Ulf (Frontiers in Microbiology, 2020)

Backbone Cyclization and Dimerization of LL-37-Derived Peptides Enhance Antimicrobial Activity and Proteolytic Stability - Gunasekera, Sunithi; Muhammad, Taj; Strömstedt, Adam A.; Rosengren, K. Johan; Göransson, Ulf (Frontiers in Microbiology, 2020)

Examination of mercaptobenzyl sulfonates as catalysts for native chemical ligation: application to the assembly of a glycosylated Glucagon-Like Peptide 1 (GLP-1) analogue - Cowper, Ben; Sze, Tsz Mei; Premdjee, Bhavesh; Bongat White, Aileen F.; Hacking, Andrew; Macmillan, Derek (Chemical Communications, 2015)
3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). , 3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances.

Examination of mercaptobenzyl sulfonates as catalysts for native chemical ligation: application to the assembly of a glycosylated Glucagon-Like Peptide 1 (GLP-1) analogue - Cowper, Ben; Sze, Tsz Mei; Premdjee, Bhavesh; Bongat White, Aileen F.; Hacking, Andrew; Macmillan, Derek (Chemical Communications, 2015)
3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). , 3/4-Mercaptobenzyl sulfonates were investigated as aryl thiol catalysts for native chemical ligation (NCL). Whilst catalysing NCL processes at a similar rate to 4-mercaptophenyl acetic acid (MPAA), the increased polarity and solubility of 3-mercaptobenzyl sulfonate in particular may favour its selection as NCL catalyst in many instances.

Ultra-Stable Peptide Scaffolds for Protein Engineering—Synthesis and Folding of the Circular Cystine Knotted Cyclotide Cycloviolacin O2 - Leta Aboye, Teshome; Clark, Richard J.; Craik, David J.; Göransson, Ulf (ChemBioChem, 2008)

Ultra-Stable Peptide Scaffolds for Protein Engineering—Synthesis and Folding of the Circular Cystine Knotted Cyclotide Cycloviolacin O2 - Leta Aboye, Teshome; Clark, Richard J.; Craik, David J.; Göransson, Ulf (ChemBioChem, 2008)

Efficient synthesis of cysteine-rich cyclic peptides through intramolecular native chemical ligation of N-Hnb-Cys peptide crypto-thioesters - Terrier, Victor P.; Delmas, Agnès F.; Aucagne, Vincent (Organic & Biomolecular Chemistry, 2017)
We herein introduce a straightforward synthetic route to cysteine-containing cyclic peptides. It is based on the intramolecular native chemical ligation of thioesters generated in situ from N -Hnb-Cys crypto-thioesters. The strategy is applied to a representative range of natural cyclic disulfide-rich peptide sequences. , We herein introduce a straightforward synthetic route to cysteine-containing cyclic peptides based on the intramolecular native chemical ligation of in situ generated thioesters. Key precursors are N -Hnb-Cys crypto-thioesters, easily synthesized by Fmoc-based SPPS. The strategy is applied to a representative range of naturally occurring cyclic disulfide-rich peptide sequences.

Efficient synthesis of cysteine-rich cyclic peptides through intramolecular native chemical ligation of N-Hnb-Cys peptide crypto-thioesters - Terrier, Victor P.; Delmas, Agnès F.; Aucagne, Vincent (Organic & Biomolecular Chemistry, 2017)
We herein introduce a straightforward synthetic route to cysteine-containing cyclic peptides. It is based on the intramolecular native chemical ligation of thioesters generated in situ from N -Hnb-Cys crypto-thioesters. The strategy is applied to a representative range of natural cyclic disulfide-rich peptide sequences. , We herein introduce a straightforward synthetic route to cysteine-containing cyclic peptides based on the intramolecular native chemical ligation of in situ generated thioesters. Key precursors are N -Hnb-Cys crypto-thioesters, easily synthesized by Fmoc-based SPPS. The strategy is applied to a representative range of naturally occurring cyclic disulfide-rich peptide sequences.

Peptide macrocyclization through amide-to-amide transpeptidation - Hemu, Xinya; Qiu, Yibo; Tam, James P. (Tetrahedron, 2014)

Peptide macrocyclization through amide-to-amide transpeptidation - Hemu, Xinya; Qiu, Yibo; Tam, James P. (Tetrahedron, 2014)

Synthesis of human GLP-1 (7–36) by chemoselective α-ketoacid–hydroxylamine peptide ligation of unprotected fragments - Wu, Jian; Ruiz-Rodríguez, Javier; Comstock, Jeanne M.; Dong, Jesse Z.; Bode, Jeffrey W. (Chemical Science, 2011)

Synthesis of human GLP-1 (7–36) by chemoselective α-ketoacid–hydroxylamine peptide ligation of unprotected fragments - Wu, Jian; Ruiz-Rodríguez, Javier; Comstock, Jeanne M.; Dong, Jesse Z.; Bode, Jeffrey W. (Chemical Science, 2011)

Chemical synthesis of a cyclotide via intramolecular cyclization of peptide O-esters - Zheng, Ji-Shen; Chang, Hao-Nan; Shi, Jing; Liu, Lei (Science China Chemistry, 2012)

Chemical synthesis of a cyclotide via intramolecular cyclization of peptide O-esters - Zheng, Ji-Shen; Chang, Hao-Nan; Shi, Jing; Liu, Lei (Science China Chemistry, 2012)

Microwave-assisted Boc-solid phase peptide synthesis of cyclic cysteine-rich peptides - Čemažar, Maša; Craik, David J. (Journal of Peptide Science, 2008)

Microwave-assisted Boc-solid phase peptide synthesis of cyclic cysteine-rich peptides - Čemažar, Maša; Craik, David J. (Journal of Peptide Science, 2008)

An Efficient Fmoc-SPPS Approach for the Generation of Thioester Peptide Precursors for Use in Native Chemical Ligation - Blanco-Canosa, Juan B.; Dawson, Philip E. (Angewandte Chemie International Edition, 2008)

An Efficient Fmoc-SPPS Approach for the Generation of Thioester Peptide Precursors for Use in Native Chemical Ligation - Blanco-Canosa, Juan B.; Dawson, Philip E. (Angewandte Chemie International Edition, 2008)

A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis - Lühmann, Tessa; Mong, Surin K.; Simon, Mark D.; Meinel, Lorenz; Pentelute, Bradley L. (Organic & Biomolecular Chemistry, 2016)
We report on the rapid-flow based synthesis and functional characterization of a H2 relaxin analog that takes advantage of perfluoroarylation-cysteine SNAr chemistry for a disulfide replacement strategy. , H2 relaxin is a pleiotropic peptide hormone with clinical potential. Here we report on the reaction and use of hexafluorobenzene as an intramolecular disulfide replacement between Cys10 and Cys15 in the A-chain of H2 relaxin. Using flow-based Fmoc solid-phase peptide synthesis methodology we were able to obtain high-quality H2 relaxin fragments that were previously reported as challenging to synthesize. Subsequent native chemical ligation and oxidative folding enabled total synthesis of both wild type H2 relaxin and a C 6 F 4 linked analog. Cell-based activity assays revealed modest activity for the C 6 F 4 linked H2 relaxin analog, albeit 100-fold reduced relative to wild type. This work demonstrates how perfluoroarylation-cysteine S N Ar chemistry may be a useful tool for the selective replacement of native disulfide bonds in proteins.

A perfluoroaromatic abiotic analog of H2 relaxin enabled by rapid flow-based peptide synthesis - Lühmann, Tessa; Mong, Surin K.; Simon, Mark D.; Meinel, Lorenz; Pentelute, Bradley L. (Organic & Biomolecular Chemistry, 2016)
We report on the rapid-flow based synthesis and functional characterization of a H2 relaxin analog that takes advantage of perfluoroarylation-cysteine SNAr chemistry for a disulfide replacement strategy. , H2 relaxin is a pleiotropic peptide hormone with clinical potential. Here we report on the reaction and use of hexafluorobenzene as an intramolecular disulfide replacement between Cys10 and Cys15 in the A-chain of H2 relaxin. Using flow-based Fmoc solid-phase peptide synthesis methodology we were able to obtain high-quality H2 relaxin fragments that were previously reported as challenging to synthesize. Subsequent native chemical ligation and oxidative folding enabled total synthesis of both wild type H2 relaxin and a C 6 F 4 linked analog. Cell-based activity assays revealed modest activity for the C 6 F 4 linked H2 relaxin analog, albeit 100-fold reduced relative to wild type. This work demonstrates how perfluoroarylation-cysteine S N Ar chemistry may be a useful tool for the selective replacement of native disulfide bonds in proteins.

Biomimetic synthesis of cyclic peptides using novel thioester surrogates: Biomimetic Synthesis of Cyclic Peptides - Hemu, Xinya; Taichi, Misako; Qiu, Yibo; Liu, Ding-Xiang; Tam, James P. (Biopolymers, 2013)

Biomimetic synthesis of cyclic peptides using novel thioester surrogates: Biomimetic Synthesis of Cyclic Peptides - Hemu, Xinya; Taichi, Misako; Qiu, Yibo; Liu, Ding-Xiang; Tam, James P. (Biopolymers, 2013)

A Thioethylalkylamido (TEA) Thioester Surrogate in the Synthesis of a Cyclic Peptide via a Tandem Acyl Shift - Taichi, Misako; Hemu, Xinya; Qiu, Yibo; Tam, James P. (Organic Letters, 2013)

A Thioethylalkylamido (TEA) Thioester Surrogate in the Synthesis of a Cyclic Peptide via a Tandem Acyl Shift - Taichi, Misako; Hemu, Xinya; Qiu, Yibo; Tam, James P. (Organic Letters, 2013)

Making Ends Meet: Chemically Mediated Circularization of Recombinant Proteins - Cowper, Ben; Craik, David J.; Macmillan, Derek (ChemBioChem, 2013)

Making Ends Meet: Chemically Mediated Circularization of Recombinant Proteins - Cowper, Ben; Craik, David J.; Macmillan, Derek (ChemBioChem, 2013)

Serine promoted synthesis of peptide thioester-precursor on solid support for native chemical ligation - Elashal, Hader E.; Sim, Yonnette E.; Raj, Monika (Chemical Science, 2017)
Fmoc solid phase peptide synthesis of peptide thioesters by displacement of the cyclic urethane moiety obtained by the selective activation of C-terminal serine. , Fmoc solid phase peptide synthesis of thioesters for the chemical synthesis of proteins via native chemical ligation is a challenge. We have developed a versatile approach for direct synthesis of peptide thioesters from a solid support utilizing Fmoc chemistry. Peptide thioester synthesis is performed by the formation of a cyclic urethane moiety via a selective reaction of the backbone amide chain with the side group of serine. The activated cyclic urethane moiety undergoes displacement by a thiol to generate the thioester directly from the solid support. Importantly, the method activates the serine residue for the synthesis of peptide thioesters; thus it is fully automated and free of the types of resins, linkers, handles, and unnatural amino acids typically needed for the synthesis of peptide thioesters using Fmoc chemistry. The resulting thioester is free of epimerization and is successfully applied for the synthesis of longer peptides using NCL.

Serine promoted synthesis of peptide thioester-precursor on solid support for native chemical ligation - Elashal, Hader E.; Sim, Yonnette E.; Raj, Monika (Chemical Science, 2017)
Fmoc solid phase peptide synthesis of peptide thioesters by displacement of the cyclic urethane moiety obtained by the selective activation of C-terminal serine. , Fmoc solid phase peptide synthesis of thioesters for the chemical synthesis of proteins via native chemical ligation is a challenge. We have developed a versatile approach for direct synthesis of peptide thioesters from a solid support utilizing Fmoc chemistry. Peptide thioester synthesis is performed by the formation of a cyclic urethane moiety via a selective reaction of the backbone amide chain with the side group of serine. The activated cyclic urethane moiety undergoes displacement by a thiol to generate the thioester directly from the solid support. Importantly, the method activates the serine residue for the synthesis of peptide thioesters; thus it is fully automated and free of the types of resins, linkers, handles, and unnatural amino acids typically needed for the synthesis of peptide thioesters using Fmoc chemistry. The resulting thioester is free of epimerization and is successfully applied for the synthesis of longer peptides using NCL.

Utilizing Copper-Mediated Deprotection of Selenazolidine for Cyclic Peptide Synthesis - Zhao, Zhenguang; Metanis, Norman (The Journal of Organic Chemistry, 2020)

Utilizing Copper-Mediated Deprotection of Selenazolidine for Cyclic Peptide Synthesis - Zhao, Zhenguang; Metanis, Norman (The Journal of Organic Chemistry, 2020)

Chemoselective sulfenylation and peptide ligation at tryptophan - Malins, Lara R.; Cergol, Katie M.; Payne, Richard J. (Chem. Sci., 2014)

Chemoselective sulfenylation and peptide ligation at tryptophan - Malins, Lara R.; Cergol, Katie M.; Payne, Richard J. (Chem. Sci., 2014)

N-Sulfanylethylanilide Peptide as a Crypto-Thioester Peptide - Sato, Kohei; Shigenaga, Akira; Tsuji, Kohei; Tsuda, Shugo; Sumikawa, Yoshitake; Sakamoto, Ken; Otaka, Akira (ChemBioChem, 2011)

N-Sulfanylethylanilide Peptide as a Crypto-Thioester Peptide - Sato, Kohei; Shigenaga, Akira; Tsuji, Kohei; Tsuda, Shugo; Sumikawa, Yoshitake; Sakamoto, Ken; Otaka, Akira (ChemBioChem, 2011)

Toward Homogeneous Erythropoietin: Chemical Synthesis of the Ala 1 −Gly 28 Glycopeptide Domain by “Alanine” Ligation - Kan, Cindy; Trzupek, John D.; Wu, Bin; Wan, Qian; Chen, Gong; Tan, Zhongping; Yuan, Yu; Danishefsky, Samuel J. (Journal of the American Chemical Society, 2009)

Toward Homogeneous Erythropoietin: Chemical Synthesis of the Ala 1 −Gly 28 Glycopeptide Domain by “Alanine” Ligation - Kan, Cindy; Trzupek, John D.; Wu, Bin; Wan, Qian; Chen, Gong; Tan, Zhongping; Yuan, Yu; Danishefsky, Samuel J. (Journal of the American Chemical Society, 2009)

Total Chemical Synthesis, Folding, and Assay of a Small Protein on a Water-Compatible Solid Support - Johnson, Erik C. B.; Durek, Thomas; Kent, Stephen B. H. (Angewandte Chemie International Edition, 2006)

Total Chemical Synthesis, Folding, and Assay of a Small Protein on a Water-Compatible Solid Support - Johnson, Erik C. B.; Durek, Thomas; Kent, Stephen B. H. (Angewandte Chemie International Edition, 2006)

Efficient Photochemical Synthesis of Peptide-α-Phenylthioesters - Pardo, Andrew; Hogenauer, Tyrone J.; Cai, Zhefeng; Vellucci, Julian A.; Castillo, Efrain M.; Dirk, Carl W.; Franz, Andreas H.; Michael, Katja (ChemBioChem, 2015)

Efficient Photochemical Synthesis of Peptide-α-Phenylthioesters - Pardo, Andrew; Hogenauer, Tyrone J.; Cai, Zhefeng; Vellucci, Julian A.; Castillo, Efrain M.; Dirk, Carl W.; Franz, Andreas H.; Michael, Katja (ChemBioChem, 2015)

Synthesis of a Self-Adjuvanting MUC1 Vaccine via Diselenide-Selenoester Ligation-Deselenization - McDonald, David M.; Hanna, Cameron C.; Ashhurst, Anneliese S.; Corcilius, Leo; Byrne, Scott N.; Payne, Richard J. (ACS Chemical Biology, 2018)

Synthesis of a Self-Adjuvanting MUC1 Vaccine via Diselenide-Selenoester Ligation-Deselenization - McDonald, David M.; Hanna, Cameron C.; Ashhurst, Anneliese S.; Corcilius, Leo; Byrne, Scott N.; Payne, Richard J. (ACS Chemical Biology, 2018)

Insights into the Finer Issues of Native Chemical Ligation: An Approach to Cascade Ligations - Tan, Zhongping; Shang, Shiying; Danishefsky, Samuel J. (Angewandte Chemie International Edition, 2010)

Insights into the Finer Issues of Native Chemical Ligation: An Approach to Cascade Ligations - Tan, Zhongping; Shang, Shiying; Danishefsky, Samuel J. (Angewandte Chemie International Edition, 2010)

Dual Kinetically Controlled Native Chemical Ligation Using a Combination of Sulfanylproline and Sulfanylethylanilide Peptide - Ding, Hao; Shigenaga, Akira; Sato, Kohei; Morishita, Ko; Otaka, Akira (Organic Letters, 2011)

Total Synthesis of Homogeneous Antifreeze Glycopeptides and Glycoproteins - Wilkinson, Brendan L.; Stone, Robin S.; Capicciotti, Chantelle J.; Thaysen-Andersen, Morten; Matthews, Jacqueline M.; Packer, Nicolle H.; Ben, Robert N.; Payne, Richard J. (Angewandte Chemie International Edition, 2012)

Dual Kinetically Controlled Native Chemical Ligation Using a Combination of Sulfanylproline and Sulfanylethylanilide Peptide - Ding, Hao; Shigenaga, Akira; Sato, Kohei; Morishita, Ko; Otaka, Akira (Organic Letters, 2011)

Total Synthesis of Homogeneous Antifreeze Glycopeptides and Glycoproteins - Wilkinson, Brendan L.; Stone, Robin S.; Capicciotti, Chantelle J.; Thaysen-Andersen, Morten; Matthews, Jacqueline M.; Packer, Nicolle H.; Ben, Robert N.; Payne, Richard J. (Angewandte Chemie International Edition, 2012)

Cysteine Promoted C-Terminal Hydrazinolysis of Native Peptides and Proteins - Adams, Anna L.; Cowper, Ben; Morgan, Rachel E.; Premdjee, Bhavesh; Caddick, Stephen; Macmillan, Derek (Angewandte Chemie International Edition, 2013)

Cysteine Promoted C-Terminal Hydrazinolysis of Native Peptides and Proteins - Adams, Anna L.; Cowper, Ben; Morgan, Rachel E.; Premdjee, Bhavesh; Caddick, Stephen; Macmillan, Derek (Angewandte Chemie International Edition, 2013)

Catalysis of Thiol–Thioester Exchange by Water-Soluble Alkyldiselenols Applied to the Synthesis of Peptide Thioesters and SEA-Mediated Ligation - Cargoët, Marine; Diemer, Vincent; Snella, Benoît; Desmet, Rémi; Blanpain, Annick; Drobecq, Hervé; Agouridas, Vangelis; Melnyk, Oleg (The Journal of Organic Chemistry, 2018)

Catalysis of Thiol–Thioester Exchange by Water-Soluble Alkyldiselenols Applied to the Synthesis of Peptide Thioesters and SEA-Mediated Ligation - Cargoët, Marine; Diemer, Vincent; Snella, Benoît; Desmet, Rémi; Blanpain, Annick; Drobecq, Hervé; Agouridas, Vangelis; Melnyk, Oleg (The Journal of Organic Chemistry, 2018)

Toward a Novel Drug To Target the EGF-EGFR Interaction: Design of Metabolically Stable Bicyclic Peptides - Guardiola, Salvador; Seco, Jesús; Varese, Monica; Díaz-Lobo, Mireia; García, Jesús; Teixidó, Meritxell; Nevola, Laura; Giralt, Ernest (ChemBioChem, 2018)

Toward a Novel Drug To Target the EGF-EGFR Interaction: Design of Metabolically Stable Bicyclic Peptides - Guardiola, Salvador; Seco, Jesús; Varese, Monica; Díaz-Lobo, Mireia; García, Jesús; Teixidó, Meritxell; Nevola, Laura; Giralt, Ernest (ChemBioChem, 2018)

Tandem ligation at X-Cys and Gly-Gly positions via an orthogonally protected auxiliary group - Spetzler, Jane C.; Hoeg-Jensen, Thomas (Bioorganic & Medicinal Chemistry, 2007)

Tandem ligation at X-Cys and Gly-Gly positions via an orthogonally protected auxiliary group - Spetzler, Jane C.; Hoeg-Jensen, Thomas (Bioorganic & Medicinal Chemistry, 2007)

Native Chemical Ligation at Valine - Haase, Christian; Rohde, Heike; Seitz, Oliver (Angewandte Chemie International Edition, 2008)

Native Chemical Ligation at Valine - Haase, Christian; Rohde, Heike; Seitz, Oliver (Angewandte Chemie International Edition, 2008)

De Novo Design To Synthesize Lanthipeptides Involving Cascade Cysteine Reactions: SapB Synthesis as an Example - Chen, Huai; Zhang, Yuan; Li, Qian-Qian; Zhao, Yu-Fen; Chen, Yong-Xiang; Li, Yan-Mei (The Journal of Organic Chemistry, 2018)

De Novo Design To Synthesize Lanthipeptides Involving Cascade Cysteine Reactions: SapB Synthesis as an Example - Chen, Huai; Zhang, Yuan; Li, Qian-Qian; Zhao, Yu-Fen; Chen, Yong-Xiang; Li, Yan-Mei (The Journal of Organic Chemistry, 2018)

Extended Sugar-Assisted Glycopeptide Ligations: Development, Scope, and Applications - Payne, Richard J.; Ficht, Simon; Tang, Sishi; Brik, Ashraf; Yang, Yu-Ying; Case, David A.; Wong, Chi-Huey (Journal of the American Chemical Society, 2007)

Extended Sugar-Assisted Glycopeptide Ligations: Development, Scope, and Applications - Payne, Richard J.; Ficht, Simon; Tang, Sishi; Brik, Ashraf; Yang, Yu-Ying; Case, David A.; Wong, Chi-Huey (Journal of the American Chemical Society, 2007)

Cyclization of the Antimicrobial Peptide Gomesin with Native Chemical Ligation: Influences on Stability and Bioactivity - Chan, Lai Yue; Zhang, Veronica M.; Huang, Yen-hua; Waters, Norman C.; Bansal, Paramjit S.; Craik, David J.; Daly, Norelle L. (ChemBioChem, 2013)

Cyclization of the Antimicrobial Peptide Gomesin with Native Chemical Ligation: Influences on Stability and Bioactivity - Chan, Lai Yue; Zhang, Veronica M.; Huang, Yen-hua; Waters, Norman C.; Bansal, Paramjit S.; Craik, David J.; Daly, Norelle L. (ChemBioChem, 2013)

Efficient one-pot cyclization/folding of Rhesus θ-defensin-1 (RTD-1) - Aboye, Teshome L.; Li, Yilong; Majumder, Subhabrata; Hao, Jinfeng; Shekhtman, Alexander; Camarero, Julio A. (Bioorganic & Medicinal Chemistry Letters, 2012)

Efficient one-pot cyclization/folding of Rhesus θ-defensin-1 (RTD-1) - Aboye, Teshome L.; Li, Yilong; Majumder, Subhabrata; Hao, Jinfeng; Shekhtman, Alexander; Camarero, Julio A. (Bioorganic & Medicinal Chemistry Letters, 2012)

Synthesis of homogeneous antifreeze glycopeptides via a ligation–desulfurisation strategy - Garner, James; Jolliffe, Katrina A.; Harding, Margaret M.; Payne, Richard J. (Chemical Communications, 2009)

Full Sequence Amino Acid Scanning of θ-Defensin RTD-1 Yields a Potent Anthrax Lethal Factor Protease Inhibitor - Li, Yilong; Gould, Andrew; Aboye, Teshome; Bi, Tao; Breindel, Leonard; Shekhtman, Alexander; Camarero, Julio A. (Journal of Medicinal Chemistry, 2017)

Synthesis of homogeneous antifreeze glycopeptides via a ligation–desulfurisation strategy - Garner, James; Jolliffe, Katrina A.; Harding, Margaret M.; Payne, Richard J. (Chemical Communications, 2009)

Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5- d ]pyrimidine-2,4(1 H ,3 H )-dione Core - Nance, Kellie D.; Days, Emily L.; Weaver, C. David; Coldren, Anastasia; Farmer, Tiffany D.; Cho, Hyekyung P.; Niswender, Colleen M.; Blobaum, Anna L.; Niswender, Kevin D.; Lindsley, Craig W. (Journal of Medicinal Chemistry, 2017)

Full Sequence Amino Acid Scanning of θ-Defensin RTD-1 Yields a Potent Anthrax Lethal Factor Protease Inhibitor - Li, Yilong; Gould, Andrew; Aboye, Teshome; Bi, Tao; Breindel, Leonard; Shekhtman, Alexander; Camarero, Julio A. (Journal of Medicinal Chemistry, 2017)

Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides - Ollivier, Nathalie; Toupy, Thomas; Hartkoorn, Ruben C.; Desmet, Rémi; Monbaliu, Jean-Christophe M.; Melnyk, Oleg (Nature Communications, 2018)

Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5- d ]pyrimidine-2,4(1 H ,3 H )-dione Core - Nance, Kellie D.; Days, Emily L.; Weaver, C. David; Coldren, Anastasia; Farmer, Tiffany D.; Cho, Hyekyung P.; Niswender, Colleen M.; Blobaum, Anna L.; Niswender, Kevin D.; Lindsley, Craig W. (Journal of Medicinal Chemistry, 2017)

Synthesis of a Selenocysteine-Containing Peptide by Native Chemical Ligation - Gieselman, Matt D.; Xie, Lili; van der Donk, Wilfred A. (Organic Letters, 2001)

Accelerated microfluidic native chemical ligation at difficult amino acids toward cyclic peptides - Ollivier, Nathalie; Toupy, Thomas; Hartkoorn, Ruben C.; Desmet, Rémi; Monbaliu, Jean-Christophe M.; Melnyk, Oleg (Nature Communications, 2018)

Convergent Glycopeptide Synthesis by Traceless Staudinger Ligation and Enzymatic Coupling - Liu, Lei; Hong, Zhang-Yong; Wong, Chi-Huey (ChemBioChem, 2006)

One-Pot Ligation-Oxidative Deselenization at Selenocysteine and Selenocystine - Mitchell, Nicholas J.; Kulkarni, Sameer S.; Malins, Lara R.; Wang, Siyao; Payne, Richard J. (Chemistry - A European Journal, 2017)

Synthesis of a Selenocysteine-Containing Peptide by Native Chemical Ligation - Gieselman, Matt D.; Xie, Lili; van der Donk, Wilfred A. (Organic Letters, 2001)

N -Linked Glycosyl Auxiliary-Mediated Native Chemical Ligation on Aspartic Acid: Application towards N -Glycopeptide Synthesis - Chai, Hua; Le Mai Hoang, Kim; Vu, Minh Duy; Pasunooti, Kalyan; Liu, Chuan-Fa; Liu, Xue-Wei (Angewandte Chemie International Edition, 2016)

Convergent Glycopeptide Synthesis by Traceless Staudinger Ligation and Enzymatic Coupling - Liu, Lei; Hong, Zhang-Yong; Wong, Chi-Huey (ChemBioChem, 2006)

One-Pot Peptide Ligation–Oxidative Cyclization Protocol for the Preparation of Short-/Medium-Size Disulfide Cyclopeptides - Spengler, Jan; Blanco-Canosa, Juan B.; Forni, Luciano; Albericio, Fernando (Organic Letters, 2018)

One-Pot Ligation-Oxidative Deselenization at Selenocysteine and Selenocystine - Mitchell, Nicholas J.; Kulkarni, Sameer S.; Malins, Lara R.; Wang, Siyao; Payne, Richard J. (Chemistry - A European Journal, 2017)

Cyclic MrIA: A Stable and Potent Cyclic Conotoxin with a Novel Topological Fold that Targets the Norepinephrine Transporter - Lovelace, Erica S.; Armishaw, Christopher J.; Colgrave, Michelle L.; Wahlstrom, Maria E.; Alewood, Paul F.; Daly, Norelle L.; Craik, David J. (Journal of Medicinal Chemistry, 2006)

N -Linked Glycosyl Auxiliary-Mediated Native Chemical Ligation on Aspartic Acid: Application towards N -Glycopeptide Synthesis - Chai, Hua; Le Mai Hoang, Kim; Vu, Minh Duy; Pasunooti, Kalyan; Liu, Chuan-Fa; Liu, Xue-Wei (Angewandte Chemie International Edition, 2016)

Expanding the scope of N → S acyl transfer in native peptide sequences - Cowper, Ben; Shariff, Leila; Chen, Wenjie; Gibson, Samantha M.; Di, Wei-Li; Macmillan, Derek (Organic & Biomolecular Chemistry, 2015)
A wider variety of Xaa-Cys motifs than originally envisaged were capable of undergoing efficient N → S acyl transfer to form thioesters and cyclic peptides, and our findings are applied to synthesis of wild-type Sunflower Trypsin Inhibitor-1 (SFTI-1). , Understanding the factors that influence N → S acyl transfer in native peptide sequences, and discovery of new reagents that facilitate it, will be key to expanding its scope and applicability. Here, through a study of short model peptides in thioester formation and cyclisation reactions, we demonstrate that a wider variety of Xaa-Cys motifs than originally envisaged are capable of undergoing efficient N → S acyl transfer. We present data for the relative rates of thioester formation and cyclisation for a representative set of amino acids, and show how this expanded scope can be applied to the production of the natural protease inhibitor Sunflower Trypsin Inhibitor-1 (SFTI-1).

One-Pot Peptide Ligation–Oxidative Cyclization Protocol for the Preparation of Short-/Medium-Size Disulfide Cyclopeptides - Spengler, Jan; Blanco-Canosa, Juan B.; Forni, Luciano; Albericio, Fernando (Organic Letters, 2018)

Cyclic MrIA: A Stable and Potent Cyclic Conotoxin with a Novel Topological Fold that Targets the Norepinephrine Transporter - Lovelace, Erica S.; Armishaw, Christopher J.; Colgrave, Michelle L.; Wahlstrom, Maria E.; Alewood, Paul F.; Daly, Norelle L.; Craik, David J. (Journal of Medicinal Chemistry, 2006)

Sunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via N→S acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5) - Shariff, Leila; Zhu, Yanan; Cowper, Ben; Di, Wei-Li; Macmillan, Derek (Tetrahedron, 2014)

Expanding the scope of N → S acyl transfer in native peptide sequences - Cowper, Ben; Shariff, Leila; Chen, Wenjie; Gibson, Samantha M.; Di, Wei-Li; Macmillan, Derek (Organic & Biomolecular Chemistry, 2015)
A wider variety of Xaa-Cys motifs than originally envisaged were capable of undergoing efficient N → S acyl transfer to form thioesters and cyclic peptides, and our findings are applied to synthesis of wild-type Sunflower Trypsin Inhibitor-1 (SFTI-1). , Understanding the factors that influence N → S acyl transfer in native peptide sequences, and discovery of new reagents that facilitate it, will be key to expanding its scope and applicability. Here, through a study of short model peptides in thioester formation and cyclisation reactions, we demonstrate that a wider variety of Xaa-Cys motifs than originally envisaged are capable of undergoing efficient N → S acyl transfer. We present data for the relative rates of thioester formation and cyclisation for a representative set of amino acids, and show how this expanded scope can be applied to the production of the natural protease inhibitor Sunflower Trypsin Inhibitor-1 (SFTI-1).

Efficient synthesis of trypsin inhibitor SFTI-1 via intramolecular ligation of peptide hydrazide - Chen, Yi-Qun; Chen, Chen-Chen; He, Yao; Yu, Mu; Xu, Lin; Tian, Chang-lin; Guo, Qing-Xiang; Shi, Jing; Zhang, Min; Li, Yi-Ming (Tetrahedron Letters, 2014)

Sunflower trypsin inhibitor (SFTI-1) analogues of synthetic and biological origin via N→S acyl transfer: potential inhibitors of human Kallikrein-5 (KLK5) - Shariff, Leila; Zhu, Yanan; Cowper, Ben; Di, Wei-Li; Macmillan, Derek (Tetrahedron, 2014)

High-Throughput Synthesis of Peptide α-Thioesters: A Safety Catch Linker Approach Enabling Parallel Hydrogen Fluoride Cleavage - Brust, Andreas; Schroeder, Christina I.; Alewood, Paul F. (ChemMedChem, 2014)

A Facile N -Mercaptoethoxyglycinamide (MEGA) Linker Approach to Peptide Thioesterification and Cyclization - Shelton, Patrick M. M.; Weller, Caroline E.; Chatterjee, Champak (Journal of the American Chemical Society, 2017)

Efficient synthesis of trypsin inhibitor SFTI-1 via intramolecular ligation of peptide hydrazide - Chen, Yi-Qun; Chen, Chen-Chen; He, Yao; Yu, Mu; Xu, Lin; Tian, Chang-lin; Guo, Qing-Xiang; Shi, Jing; Zhang, Min; Li, Yi-Ming (Tetrahedron Letters, 2014)

Direct Peptide Cyclization and One-Pot Modification Using the MeDbz Linker - Gless, Bengt H.; Olsen, Christian A. (The Journal of Organic Chemistry, 2018)

High-Throughput Synthesis of Peptide α-Thioesters: A Safety Catch Linker Approach Enabling Parallel Hydrogen Fluoride Cleavage - Brust, Andreas; Schroeder, Christina I.; Alewood, Paul F. (ChemMedChem, 2014)

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease - Cobos Caceres, Claudia; Bansal, Paramjit S.; Navarro, Severine; Wilson, David; Don, Laurianne; Giacomin, Paul; Loukas, Alex; Daly, Norelle L. (Journal of Biological Chemistry, 2017)

A Facile N -Mercaptoethoxyglycinamide (MEGA) Linker Approach to Peptide Thioesterification and Cyclization - Shelton, Patrick M. M.; Weller, Caroline E.; Chatterjee, Champak (Journal of the American Chemical Society, 2017)

Direct Peptide Cyclization and One-Pot Modification Using the MeDbz Linker - Gless, Bengt H.; Olsen, Christian A. (The Journal of Organic Chemistry, 2018)

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease - Cobos Caceres, Claudia; Bansal, Paramjit S.; Navarro, Severine; Wilson, David; Don, Laurianne; Giacomin, Paul; Loukas, Alex; Daly, Norelle L. (Journal of Biological Chemistry, 2017)

Investigation of peptide thioester formation via N → Se acyl transfer: N → Se ACYL TRANSFER - Adams, Anna L.; Macmillan, Derek (Journal of Peptide Science, 2013)

Total Synthesis of Daptomycin by Cyclization via a Chemoselective Serine Ligation - Lam, Hiu Yung; Zhang, Yinfeng; Liu, Han; Xu, Jianchao; Wong, Clarence T. T.; Xu, Ci; Li, Xuechen (Journal of the American Chemical Society, 2013)

Metal-Assisted Folding of Prolinomycin Allows Facile Design of Functional Peptides - Hosseini, Azade S.; Wang, Wenjian; Haeffner, Fredrik; Gao, Jianmin (ChemBioChem, 2017)

Synthesis and antibacterial studies of teixobactin analogues with non-isostere substitution of enduracididine - Jin, Kang; Po, Kathy Hiu Laam; Kong, Wang Yeuk; Lo, Chung Hei; Lo, Chun Wah; Lam, Ho Yin; Sirinimal, Amaya; Reuven, Jonathan Avraham; Chen, Sheng; Li, Xuechen (Bioorganic & Medicinal Chemistry, 2018)

Investigation of peptide thioester formation via N → Se acyl transfer: N → Se ACYL TRANSFER - Adams, Anna L.; Macmillan, Derek (Journal of Peptide Science, 2013)

Free-Radical-Based, Specific Desulfurization of Cysteine: A Powerful Advance in the Synthesis of Polypeptides and Glycopolypeptides - Wan, Qian; Danishefsky, Samuel J. (Angewandte Chemie International Edition, 2007)

Total Synthesis of Daptomycin by Cyclization via a Chemoselective Serine Ligation - Lam, Hiu Yung; Zhang, Yinfeng; Liu, Han; Xu, Jianchao; Wong, Clarence T. T.; Xu, Ci; Li, Xuechen (Journal of the American Chemical Society, 2013)

Synthesis of selenocysteine-containing cyclic peptides via tandem N -to- S acyl migration and intramolecular selenocysteine-mediated native chemical ligation - Shimodaira, Shingo; Takei, Toshiki; Hojo, Hironobu; Iwaoka, Michio (Chemical Communications, 2018)
Cyclic selenocysteine-containing peptides were synthesized via one-pot tandem conversion of N -alkylcysteine-containing selenopeptides. , Selenocysteine-containing cyclic 8-mer peptides, which were designed to mimic the plausible catalytic tetrad of glutathione peroxidase, were successfully synthesized in one pot via tandem N -to- S acyl migration of N -alkylcysteine (NAC)-containing selenopeptides and intramolecular selenocysteine-mediated native chemical ligation (Sec-NCL) of the generated thioesters.

Metal-Assisted Folding of Prolinomycin Allows Facile Design of Functional Peptides - Hosseini, Azade S.; Wang, Wenjian; Haeffner, Fredrik; Gao, Jianmin (ChemBioChem, 2017)

Direct synthesis of cyclic lipopeptides using intramolecular native chemical ligation and thiol–ene CLipPA chemistry - Yim, Victor V.; Kavianinia, Iman; Cameron, Alan J.; Harris, Paul W. R.; Brimble, Margaret A. (Organic & Biomolecular Chemistry, 2020)
Cyclic lipopeptides are often challenging synthetic targets. A synthetic approach is presented that employs cyclisation by intramolecular native chemical ligation (NCL) and a thiol–ene “CLipPA” reaction to afford S -lipidated analogues of iturin A. , Naturally occurring cyclic lipopeptides exhibit a diverse range of biological activities and possess several favourable properties. Chemically synthesising and modifying these natural compounds can alter their biological and physical properties. Cyclic lipopeptides are often difficult to synthesise, especially when the lipid moiety is directly attached to the cyclic scaffold. The construction of a series of cyclic lipopeptide analogues of the antifungal peptide iturin A is reported herein. The synthesis of the parent peptide macrocycle was achieved using native chemical ligation (NCL), whereupon the regenerated free thiol was used to attach a lipid moiety using Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology.

Facile Synthesis of Peptidyl Salicylaldehyde Esters and Its Use in Cyclic Peptide Synthesis - Zhao, Jun-Feng; Zhang, Xiao-Hong; Ding, Ying-Jie; Yang, Yong-Sheng; Bi, Xiao-Bao; Liu, Chuan-Fa (Organic Letters, 2013)

Effective synthesis of kynurenine-containing peptides via on-resin ozonolysis of tryptophan residues: synthesis of cyclomontanin B - Wong, Clarence T. T.; Lam, Hiu Yung; Li, Xuechen (Organic & Biomolecular Chemistry, 2013)

Synthesis and antibacterial studies of teixobactin analogues with non-isostere substitution of enduracididine - Jin, Kang; Po, Kathy Hiu Laam; Kong, Wang Yeuk; Lo, Chung Hei; Lo, Chun Wah; Lam, Ho Yin; Sirinimal, Amaya; Reuven, Jonathan Avraham; Chen, Sheng; Li, Xuechen (Bioorganic & Medicinal Chemistry, 2018)

Effective synthesis of cyclic peptide yunnanin C and analogues via Ser/Thr ligation (STL)-mediated peptide cyclization - Wong, Clarence T.T.; Lam, Hiu Yung; Li, Xuechen (Tetrahedron, 2014)

Free-Radical-Based, Specific Desulfurization of Cysteine: A Powerful Advance in the Synthesis of Polypeptides and Glycopolypeptides - Wan, Qian; Danishefsky, Samuel J. (Angewandte Chemie International Edition, 2007)

Investigation of Cysteine as an Activator of Side-Chain N→S Acyl Transfer and Tail-to-Side-Chain Cyclization - Castillo-Pazos, Durbis; Macmillan, Derek (Synlett, 2017)
N→S Acyl transfer is a popular method for the postsynthesis production of peptide C α-thioesters for use in native chemical ligation and for the synthesis of head-to-tail cyclic peptides. Meanwhile thioester formation at the side chain of aspartic or glutamic acids, leading to tail-to-side-chain-cyclized species, is less common. Herein we explore the potential for cysteine to function as a latent thioester when appended to the side chain of glutamic acid. Initial insights gained through study of C-terminal β-alanine as a model for the increased chain length were ultimately applied to peptide macrocyclization. Our results emphasize the increased barrier to acyl transfer at the glutamic acid side chain and indicate how a slow reaction, facilitated by cysteine itself, may be accelerated by fine-tuning of the stereoelectronic environment.

Synthesis of selenocysteine-containing cyclic peptides via tandem N -to- S acyl migration and intramolecular selenocysteine-mediated native chemical ligation - Shimodaira, Shingo; Takei, Toshiki; Hojo, Hironobu; Iwaoka, Michio (Chemical Communications, 2018)
Cyclic selenocysteine-containing peptides were synthesized via one-pot tandem conversion of N -alkylcysteine-containing selenopeptides. , Selenocysteine-containing cyclic 8-mer peptides, which were designed to mimic the plausible catalytic tetrad of glutathione peroxidase, were successfully synthesized in one pot via tandem N -to- S acyl migration of N -alkylcysteine (NAC)-containing selenopeptides and intramolecular selenocysteine-mediated native chemical ligation (Sec-NCL) of the generated thioesters.

Direct synthesis of cyclic lipopeptides using intramolecular native chemical ligation and thiol–ene CLipPA chemistry - Yim, Victor V.; Kavianinia, Iman; Cameron, Alan J.; Harris, Paul W. R.; Brimble, Margaret A. (Organic & Biomolecular Chemistry, 2020)
Cyclic lipopeptides are often challenging synthetic targets. A synthetic approach is presented that employs cyclisation by intramolecular native chemical ligation (NCL) and a thiol–ene “CLipPA” reaction to afford S -lipidated analogues of iturin A. , Naturally occurring cyclic lipopeptides exhibit a diverse range of biological activities and possess several favourable properties. Chemically synthesising and modifying these natural compounds can alter their biological and physical properties. Cyclic lipopeptides are often difficult to synthesise, especially when the lipid moiety is directly attached to the cyclic scaffold. The construction of a series of cyclic lipopeptide analogues of the antifungal peptide iturin A is reported herein. The synthesis of the parent peptide macrocycle was achieved using native chemical ligation (NCL), whereupon the regenerated free thiol was used to attach a lipid moiety using Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technology.

Facile Synthesis of Peptidyl Salicylaldehyde Esters and Its Use in Cyclic Peptide Synthesis - Zhao, Jun-Feng; Zhang, Xiao-Hong; Ding, Ying-Jie; Yang, Yong-Sheng; Bi, Xiao-Bao; Liu, Chuan-Fa (Organic Letters, 2013)

Coupling of sterically demanding peptides by β-thiolactone-mediated native chemical ligation - Chen, Huan; Xiao, Yunxian; Yuan, Ning; Weng, Jiaping; Gao, Pengcheng; Breindel, Leonard; Shekhtman, Alexander; Zhang, Qiang (Chemical Science, 2018)
β-Thiolactones have enabled the sterically demanding peptidyl ligations of Val–Leu, Val–Val and Val–Pro using a one-pot NCL and desulfurization protocol. , The ligation of sterically demanding peptidyl sites such as those involving Val–Val and Val–Pro linkages has proven to be extremely challenging with conventional NCL methods that rely on exogenous thiol additives. Herein, we report an efficient β-thiolactone-mediated additive-free NCL protocol that enables the establishment of these connections in good yield. The rapid NCL was followed by in situ desulfurization. Reaction rates between β-thiolactones and conventional thioesters towards NCL were also investigated, and direct aminolysis was ruled out as a possible pathway. Finally, the potent cytotoxic cyclic-peptide axinastatin 1 has been prepared using the developed methodology.

Effective synthesis of kynurenine-containing peptides via on-resin ozonolysis of tryptophan residues: synthesis of cyclomontanin B - Wong, Clarence T. T.; Lam, Hiu Yung; Li, Xuechen (Organic & Biomolecular Chemistry, 2013)

Effective synthesis of cyclic peptide yunnanin C and analogues via Ser/Thr ligation (STL)-mediated peptide cyclization - Wong, Clarence T.T.; Lam, Hiu Yung; Li, Xuechen (Tetrahedron, 2014)

Investigation of Cysteine as an Activator of Side-Chain N→S Acyl Transfer and Tail-to-Side-Chain Cyclization - Castillo-Pazos, Durbis; Macmillan, Derek (Synlett, 2017)
N→S Acyl transfer is a popular method for the postsynthesis production of peptide C α-thioesters for use in native chemical ligation and for the synthesis of head-to-tail cyclic peptides. Meanwhile thioester formation at the side chain of aspartic or glutamic acids, leading to tail-to-side-chain-cyclized species, is less common. Herein we explore the potential for cysteine to function as a latent thioester when appended to the side chain of glutamic acid. Initial insights gained through study of C-terminal β-alanine as a model for the increased chain length were ultimately applied to peptide macrocyclization. Our results emphasize the increased barrier to acyl transfer at the glutamic acid side chain and indicate how a slow reaction, facilitated by cysteine itself, may be accelerated by fine-tuning of the stereoelectronic environment.

Visible-Light-Induced Specific Desulfurization of Cysteinyl Peptide and Glycopeptide in Aqueous Solution - Gao, Xiao-Fei; Du, Jing-Jing; Liu, Zheng; Guo, Jun (Organic Letters, 2016)

Coupling of sterically demanding peptides by β-thiolactone-mediated native chemical ligation - Chen, Huan; Xiao, Yunxian; Yuan, Ning; Weng, Jiaping; Gao, Pengcheng; Breindel, Leonard; Shekhtman, Alexander; Zhang, Qiang (Chemical Science, 2018)
β-Thiolactones have enabled the sterically demanding peptidyl ligations of Val–Leu, Val–Val and Val–Pro using a one-pot NCL and desulfurization protocol. , The ligation of sterically demanding peptidyl sites such as those involving Val–Val and Val–Pro linkages has proven to be extremely challenging with conventional NCL methods that rely on exogenous thiol additives. Herein, we report an efficient β-thiolactone-mediated additive-free NCL protocol that enables the establishment of these connections in good yield. The rapid NCL was followed by in situ desulfurization. Reaction rates between β-thiolactones and conventional thioesters towards NCL were also investigated, and direct aminolysis was ruled out as a possible pathway. Finally, the potent cytotoxic cyclic-peptide axinastatin 1 has been prepared using the developed methodology.

Visible-Light-Induced Specific Desulfurization of Cysteinyl Peptide and Glycopeptide in Aqueous Solution - Gao, Xiao-Fei; Du, Jing-Jing; Liu, Zheng; Guo, Jun (Organic Letters, 2016)