Combining Chemical Protein Synthesis and Random Nonstandard Peptides Integrated Discovery for Modulating Biological Processes

Abstract

This work describes ab initio RaPID selection and consequent rational mutagenesis for the selection process to improve the binding affinity of macrocyclic peptide toward Lys48-linked di-Ub.

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315

“…Then, the canonical N- or/and C- terminal modifications, as well as the inverse-peptide strategy were conducted on LTX-315. Recently, D-type peptides have been considered as promising anticancer agents due to their striking hydrolysis-resistant properties and low immunogenicity, compared with their enantiomeric counterparts. − Thus, we also performed the first D-type amino acid substitution for LTX-315 and derived peptides. Especially, the in vivo and in vitro anticancer tests were conducted to evaluate the anticancer activity of synthetic peptides.…”

Selective Peptide Cysteine Manipulation on Demand and Difficult Protein Chemical Synthesis Enabled by Controllable Acidolysis of N,S‐Benzylidene Thioacetals

“…[15][16][17] These chemically synthesized peptides/proteins in homogeneous forms provide unique opportunity to unveil the role of site-specific post-translational modifications (PTMs) in fundamental chemical biology and to develop the next-generation peptide/protein-based therapeutic modalities. [18,19] Albeit these developments, there are still many important peptides/proteins not directly achievable by simple SPPS and peptide ligation, requiring complicated assisting strategies and sometimes even compromising detour of residue mutation for improving their synthetic performance. [20,21] Establishing more simple and general strategy to tackle those challenges is still of continued interest.…”

Expanding Bioactive Fragment Space with the Generated Database GDB-13s

“…7,8 These libraries contain billions of molecules, as in ZINC 9 or the Enamine REAL database, 10,11 up to hundreds of billions of molecules in DNA encoded libraries, 12−15 or even much larger numbers of peptides and cyclic peptides in phage or ribosome display libraries. 16,17 Such molecules often break Lipinski's rule of five but can nevertheless be developed as drugs. 18,19 Despite the impressive numbers of molecules in the abovementioned databases, these molecules are obtained by combining a limited set of building blocks, typically up to thousands (only 20 for genetically encoded peptides), which severely limits fragment diversity.…”

“…Medicinal chemistry becomes an increasingly retrospective activity as public databases such as PubChem and ChEMBL list increasing numbers of known drug-like molecules and their biological activity, from which new analogues can be derived. Nevertheless, introducing chemical novelty in new drugs is important because it can help to address new target types and overcome the limitations of classical molecular series in terms of physicochemical properties, selectivity, toxicity, and metabolism, as well as to secure intellectual property and the possibility of commercial development. − Currently, innovation focuses on exploiting very large libraries of screening compounds obtained by combining known building blocks using known chemistry. , These libraries contain billions of molecules, as in ZINC or the Enamine REAL database, , up to hundreds of billions of molecules in DNA encoded libraries, − or even much larger numbers of peptides and cyclic peptides in phage or ribosome display libraries. , Such molecules often break Lipinski’s rule of five but can nevertheless be developed as drugs. , …”

“… 7 , 8 These libraries contain billions of molecules, as in ZINC 9 or the Enamine REAL database, 10 , 11 up to hundreds of billions of molecules in DNA encoded libraries, 12 − 15 or even much larger numbers of peptides and cyclic peptides in phage or ribosome display libraries. 16 , 17 Such molecules often break Lipinski’s rule of five but can nevertheless be developed as drugs. 18 , 19 …”