Article
Biochemistry & Molecular Biology
Manuel G. Ricardo, Yadiel Vazquez-Mena, Yuleidys Iglesias-Morales, Ludger A. Wessjohann, Daniel G. Rivera
Summary: Peptide stapling technology, specifically through multicomponent macrocyclization, is a mature approach for introducing conformational constraints and additional functionalities to helical peptides. This study explores the potential of double Ugi multicomponent stapling approach in producing helical peptides from unstructured sequences, providing insights into structural factors influencing helicity and potential for diversifying molecular tethers.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Richard Morewood, Christoph Nitsche
Summary: Stapling peptides can improve their potential as drug candidates, and the activity can be adjusted by tailored linkers. In the search for inhibitors of the Zika virus protease, the length of the linker in the peptide staple was crucial for maximizing activity.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Richard Morewood, Christoph Nitsche
Summary: Constrained peptides are promising next-generation therapeutics, and peptide stapling is an effective technique to improve the biological activity and metabolic stability of constrained macrocycles. A biocompatible two-component stapling approach based on 2,6-dicyanopyridine and a pseudo-cysteine amino acid allows for efficient stapling either during solid-phase synthesis or following isolation of linear peptides. The orthogonal stapling reaction in aqueous solution at physiological pH enables its direct use in biochemical assays, and successful identification of constrained peptide inhibitors has been demonstrated through a small screening campaign targeting the Zika virus protease NS2B-NS3.
Article
Chemistry, Organic
Yue Zhang, Ruijuan Yin, Hao Jiang, Chaoming Wang, Xiao Wang, Dongping Wang, Kai Zhang, Rilei Yu, Xuechen Li, Tao Jiang
Summary: In this study, a new method for peptide stapling using bifunctional triazine moieties was developed. This method efficiently stabilizes unprotected peptides by conjugating to the phenolic hydroxyl groups of tyrosine. The application of this method to the RGD peptide, which targets integrins, showed significantly improved plasma stability and integrin-targeting ability.
Article
Multidisciplinary Sciences
Bo Li, Lan Wang, Xiangxiang Chen, Xin Chu, Hong Tang, Jie Zhang, Gang He, Li Li, Gong Chen
Summary: In this study, a method for macrocyclization of two free-amine-containing residues in mild conditions is disclosed. This method can efficiently generate complex peptide structures, expanding the toolbox for peptide chemistry.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Maria J. S. A. Silva, Helio Faustino, Jaime A. S. Coelho, Maria V. Pinto, Adelaide Fernandes, Ismael Companon, Francisco Corzana, Gilles Gasser, Pedro M. P. Gois
Summary: NHS-activated acrylamides, combining Michael acceptors and NHS activated esters, offer fast and chemoselective amino-sulfhydryl stapling on peptides and proteins under aqueous conditions, showing versatility and compatibility with other cysteine selective reagents for orthogonal dual-modifications. This strategy allows for late-stage functionalization of bioconjugates with various molecules, demonstrating a powerful tool in designing functional peptides and proteins.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Baobao Chen, Chao Liu, Wei Cong, Fei Gao, Yan Zou, Li Su, Lei Liu, Alexander Hillisch, Lutz Lehmann, Donald Bierer, Xiang Li, Hong-Gang Hu
Summary: This study describes the rational design and efficient synthesis of cyclobutane-based conformationally constrained amino acids E7 and Z7 for peptide stapling. The E7-E7 geometry-specific stapled peptides obtained showed higher alpha-helicity and stronger biological activity, demonstrating the potential of this methodology to expand the scope of peptide stapling strategy.
Article
Chemistry, Multidisciplinary
Baobao Chen, Chao Liu, Wei Cong, Fei Gao, Yan Zou, Li Su, Lei Liu, Alexander Hillisch, Lutz Lehmann, Donald Bierer, Xiang Li, Hong-Gang Hu
Summary: This study describes the rational design and efficient synthesis of cyclobutane-based conformationally constrained amino acids E7 and Z7. These amino acids were used for peptide stapling, resulting in the formation of E7-E7 geometry-specific stapled peptides. The results show that E7-E7 stapled peptides exhibit higher alpha-helicity and stronger biological activity compared to canonical hydrocarbon stapled peptides.
Article
Chemistry, Multidisciplinary
Bo Li, Hong Tang, Aneta Turlik, Zhao Wan, Xiao-Song Xue, Li Li, Xiaoxiao Yang, Jiuyuan Li, Gang He, Kendall N. Houk, Gong Chen
Summary: A simple and powerful strategy has been developed for stapling native peptides at lysine residues with formaldehyde by the cooperation of nearby tyrosine or arginine residues. This method allows for efficient and residue-selective stapling reactions under mild conditions, generating linchpins with distinct physiochemical properties. Unique control of position-selectivity for substrates bearing multiple reaction sites can be achieved through reactivity readily built in the peptide sequence.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Dhanya Karipal Padinjare Veedu, Luke A. Connal, Lara R. Malins
Summary: In this study, an electrochemical method for peptide late-stage modification using amidic side-chains is developed. The method enables the modification of glutamine residues and the introduction of high-value functionalities through electroauxiliary-assisted oxidation. The applicability of the method to complex peptide systems is demonstrated, as well as its potential for peptide stapling and functionalization.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Qing Yu, Leiyang Bai, Xuefeng Jiang
Summary: In this study, a disulfide click strategy was developed to enhance the metabolic stability and cellular permeability of therapeutic peptides. Using a library of stapling reagents, short peptides were bridged to form macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited improved anti-cancer activity and could be cleaved back to their native forms with the assistance of a specific compound.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Bichao Song, Xueying Guo, Li Yang, Haiyue Yu, Xinlei Zong, Xiujuan Liu, Hao Wang, Zhongliang Xu, Zhenyang Lin, Weibo Yang
Summary: Inspired by the C-H oxidation mechanism of cytochromes P450, a practical Rh-III-catalyzed acylmethylation macrocyclization via C-H/O-2 dual activation has been developed. The macrocyclization process is facilitated by a synergic coordination from pyridine and ester group. This unique reaction mode differs from established olefination and alkylation paths, and its mechanism has been revealed through density functional theory (DFT) calculations and control experiments. The newly achieved acylmethylation macrocyclic products and their derivatives exhibit potent anti-H1N1 bioactivity, which may lead to the discovery of novel anti-H1N1 macrocyclic leading compounds.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Multidisciplinary
Paolo Dognini, Talhat Chaudhry, Giulia Scagnetti, Michele Assante, George S. M. Hanson, Kehinde Ross, Francesca Giuntini, Christopher R. Coxon
Summary: This study presents a method for peptide cyclisation using polyfluorinated aromatic reagents and thiolates through nucleophilic aromatic substitution (SNAr). The resulting peptide scaffolds offer new possibilities for 3D peptide architectures. The method demonstrates chemoselectivity and wide applicability, allowing for stapling and multicyclisation of non-protected peptides. Additionally, a porphyrin-templated stapled peptide with skin cell penetrating ability and intrinsic fluorescence was developed.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Review
Biochemical Research Methods
Daniel G. Rivera, Manuel G. Ricardo, Aldrin V. Vasco, Ludger A. Wessjohann, Erik V. Van der Eycken
Summary: Solid-phase synthesis and multicomponent reactions serve different purposes, with the former mainly used for the automated synthesis of large molecules and the latter for generating diversity in skeletal and appendage structures. While on-resin MCRs were initially employed for library construction, the current focus has shifted towards the derivatization of peptides and oligonucleotides.
Article
Chemistry, Organic
Aldrin V. Vasco, Leonardo G. Ceballos, Ludger A. Wessjohann, Daniel G. Rivera
Summary: The replacement of the disulfide bridge by other side chain linkages is a method for developing cyclic peptide drugs. This study describes a method on resin that enables the substitution of the disulfide bond with a tertiary lactam bridge and allows the addition of various exocyclic moieties. Conformational analysis in comparison with octreotide provides important information on the functionalization type for mimicking the bioactive peptide.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Manuel G. Ricardo, Celia G. Moya, Carlos S. Perez, Andrea Porzel, Ludger A. Wessjohann, Daniel G. Rivera
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2020)
Article
Chemistry, Medicinal
Leslie Reguera, Daniel G. Rivera
Review
Chemistry, Applied
Gerardo M. Ojeda-Carralero, Leonardo G. Ceballos, Julieta Coro, Daniel G. Rivera
ACS COMBINATORIAL SCIENCE
(2020)
Editorial Material
Chemistry, Inorganic & Nuclear
Daniel G. Rivera
INORGANIC CHEMISTRY
(2020)
Editorial Material
Chemistry, Organic
Daniel G. Rivera
JOURNAL OF ORGANIC CHEMISTRY
(2020)
Editorial Material
Chemistry, Organic
Daniel G. Rivera
Editorial Material
Chemistry, Inorganic & Nuclear
Daniel G. Rivera
Article
Biochemistry & Molecular Biology
Amelia A. Fuller, Amy B. Dounay, Douglas Schirch, Daniel G. Rivera, Karl A. Hansford, Alysha G. Elliott, Johannes Zuegg, Matthew A. Cooper, Mark A. T. Blaskovich, Jacob R. Hitchens, Sarah Burris-Hiday, Kristiana Tenorio, Yanira Mendez, J. Geno Samaritoni, Martin J. O'Donnell, William L. Scott
ACS CHEMICAL BIOLOGY
(2020)
Review
Biochemical Research Methods
Daniel G. Rivera, Manuel G. Ricardo, Aldrin V. Vasco, Ludger A. Wessjohann, Erik V. Van der Eycken
Summary: Solid-phase synthesis and multicomponent reactions serve different purposes, with the former mainly used for the automated synthesis of large molecules and the latter for generating diversity in skeletal and appendage structures. While on-resin MCRs were initially employed for library construction, the current focus has shifted towards the derivatization of peptides and oligonucleotides.
Article
Chemistry, Organic
Aldrin V. Vasco, Leonardo G. Ceballos, Ludger A. Wessjohann, Daniel G. Rivera
Summary: The replacement of the disulfide bridge by other side chain linkages is a method for developing cyclic peptide drugs. This study describes a method on resin that enables the substitution of the disulfide bond with a tertiary lactam bridge and allows the addition of various exocyclic moieties. Conformational analysis in comparison with octreotide provides important information on the functionalization type for mimicking the bioactive peptide.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Aldrin V. Vasco, Yanira Mendez, Celia Gonzalez, Carlos S. Perez, Leslie Reguera, Ludger A. Wessjohann, Daniel G. Rivera
Summary: Macrocyclization of peptides is a common method to fix bioactive conformations and enhance their pharmacological properties. Macrobicyclic peptides have attracted attention due to their ability to mimic protein structures and serve as important components of peptide-drug conjugates. In this study, we develop novel synthetic strategies for two types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced to produce interconnected beta-turns, allowing the formation and dimerization of two macrocyclic rings in a single step. Additionally, an on-resin double stapling strategy is described to assemble lactam-bridged macrobicycles with stable tertiary folds.
Article
Chemistry, Inorganic & Nuclear
Leslie Reguera, Arely Cano, Joelis Rodriguez-Hernandez, Daniel G. Rivera, Erik V. Van der Eycken, Daniel Ramirez-Rosales, Edilso Reguera
DALTON TRANSACTIONS
(2020)
Article
Chemistry, Organic
Aldrin V. Vasco, Celia G. Moya, Stefan GrOger, Wolfgang Brandt, Jochen Balbach, Carlos S. Perez, Ludger A. Wessjohann, Daniel G. Rivera
ORGANIC & BIOMOLECULAR CHEMISTRY
(2020)
Review
Chemistry, Multidisciplinary
Daniel G. Rivera, Gerardo M. Ojeda-Carralero, Leslie Reguera, Erik V. Van der Eycken
CHEMICAL SOCIETY REVIEWS
(2020)
Article
Chemistry, Multidisciplinary
Radell Echemendia, Gustavo P. da Silva, Meire Y. Kawamura, Alexander F. de la Torre, Arlene G. Correa, Marco A. B. Ferreira, Daniel G. Rivera, Marcio W. Paixao
CHEMICAL COMMUNICATIONS
(2019)