Biphenyl-dihydrothiazole-cyclized peptide libraries for peptide ligand and drug discovery

Science China Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

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Engineering tRNAs for the Ribosomal Translation of Non-proteinogenic Monomers

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(10), P. 6444 - 6500

Published: April 30, 2024

Ribosome-dependent protein biosynthesis is an essential cellular process mediated by transfer RNAs (tRNAs). Generally, ribosomally synthesized proteins are limited to the 22 proteinogenic amino acids (pAAs: 20 l-α-amino present in standard genetic code, selenocysteine, and pyrrolysine). However, engineering tRNAs for ribosomal incorporation of non-proteinogenic monomers (npMs) as building blocks has led creation unique polypeptides with broad applications biology, material science, spectroscopy, pharmaceuticals. Ribosomal polymerization these engineered presents a variety challenges biochemists, translation efficiency fidelity often insufficient when employing npMs. In this Review, we will focus on methodologies overcome issues explore recent advances both vitro vivo. These efforts include increasing orthogonality, recruiting factors, expanded codes. After our review biochemical optimizations tRNAs, provide examples their use code manipulation, discovery bioactive macrocyclic peptides containing Finally, analysis current state tRNA presented, along existing future perspectives field.

Language: Английский

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The coming of age of cyclic peptide drugs: an update on discovery technologies

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(8), P. 961 - 973

Published: June 14, 2024

Introduction Cyclic peptides are an established class of pharmaceuticals, with the ability to bind a broader range protein targets than traditional small molecules while also being capable oral availability and cell penetration. Historically, cyclic peptide drugs have been discovered almost exclusively through natural product mining approaches; however, last two decades seen development display screening approaches rapidly identifying de novo (i.e. not derived) ligands interest.

Language: Английский

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From lead to market: chemical approaches to transform peptides into therapeutics

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(21), P. 12213 - 12241

Published: Oct. 25, 2024

Technological advances and breakthrough developments in the pharmaceutical field are knocking at door of "undruggable" fortress with increasing insistence. Notably, 21st century has seen emergence macrocyclic compounds, among which cyclic peptides particular interest. This new class potential drug candidates occupies vast chemical space between classic small-molecule drugs larger protein-based therapeutics, such as antibodies. As research toward clinical targets that have long been considered inaccessible, well-suited to tackle these challenges a post-rule 5 landscape. Facilitating their discovery is an arsenal high-throughput screening methods exploit massive randomized libraries genetically encoded compounds. These techniques benefit from incorporation non-natural moieties, non- proteinogenic amino acids or stabilizing hydrocarbon staples. Exploiting features for strategic architectural design challenging protein–protein interactions, resisted efforts. Review summarizes basic principles recent main focuses on specific deployment targeting undruggable space. A focus placed development guidelines cyclization structural stabilization resulting success stories achieved against well-known inaccessible targets.

Language: Английский

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Large Libraries of Structurally Diverse Macrocycles Suitable for Membrane Permeation

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(26)

Published: April 11, 2024

Macrocycles offer an attractive format for drug development due to their good binding properties and potential cross cell membranes. To efficiently identify macrocyclic ligands new targets, methods the synthesis screening of large combinatorial libraries small cyclic peptides were developed, many them using thiol groups efficient peptide macrocyclization. However, a weakness these is that invariant thiol-containing building blocks such as cysteine are used, resulting in region does not contribute library diversity but increases molecule size. Herein, we synthesized series structurally diverse elements used 2,688-member small, peptidic macrocycles with unprecedented skeletal complexity. We then this discover potent thrombin plasma kallikrein inhibitors, some also demonstrating favorable membrane permeability. X-ray structure analysis macrocycle-target complexes showed size shape newly developed key binding. The strategy presented work significantly enhance structural by allowing modifications previously macrocycles, which may be broadly applied permeable therapeutics.

Language: Английский

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Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

Published: June 10, 2024

Expanding the chemical and structural complexity of genetically encoded peptides remains a challenge in peptide therapeutics discovery. Here we report that linear with reactive β- or γ-keto amide at their N-termini can be synthesized ribosomally using vitro translation methods. We show carrying an N-terminal β-keto converted into diverse heterocyclic quinoline-peptide hybrids via Friedländer reactions variety 2-aminoarylcarbonyl co-substrates. Reactions appropriately substituted 2-aminobenzophenones generated stable biaryl atropisomeric axes. In vitro-translated both internal 2-aminoacetophenone motif undergo intramolecular macrocyclization embed quinoline pharmacophore directly within macrocyclic backbone. The introduction ketide building blocks materials post-translational derivatization carbonyl chemistry simultaneously expands diversity provides paradigm for programmed synthesis peptide-derived more closely resemble complex natural products.

Language: Английский

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Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 13020 - 13093

Published: Nov. 14, 2024

The development of potent, specific, and pharmacologically viable chemical probes therapeutics is a central focus biology therapeutic development. However, significant portion predicted disease-causal proteins have proven resistant to targeting by traditional small molecule biologic modalities. Many these so-called "undruggable" targets feature extended, dynamic protein-protein protein-nucleic acid interfaces that are their roles in normal diseased signaling pathways. Here, we discuss the synthetically stabilized peptide protein mimetics as an ever-expanding powerful region space tackle undruggable targets. These molecules aim combine synthetic tunability pharmacologic properties typically associated with binding footprints, affinities specificities biologics. In this review, historical emerging platforms approaches design, screen, select optimize "designer" peptidomimetics We examine inspiration design different classes designer peptidomimetics: (i) macrocyclic peptides, (ii) side chain (iii) non-natural peptidomimetics, (iv) proteomimetics, notable examples application challenging biomolecules. Finally, summarize key learnings remaining challenges for become useful historically

Language: Английский

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Recent advances in peptide macrocyclization strategies

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Owing to their special spatial structures, peptide-based macrocycles have recently shown tremendous promise in multidisciplinary research ranging from potent antibiotics against resistant strains functional biomaterials with novel properties.

Language: Английский

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A membrane permeability database for nonpeptidic macrocycles

Scientific Data, Journal Year: 2025, Volume and Issue: 12(1)

Published: Jan. 3, 2025

Abstract The process of developing new drugs is arduous and costly, particularly for targets classified as “difficult-to-drug.” Macrocycles show a particular ability to modulate difficult-to-drug targets, including protein-protein interactions, while still allowing oral administration. However, the determination membrane permeability, critical reaching intracellular bioavailability, laborious expensive. In silico methods are cost-effective alternative, enabling predictions prior compound synthesis. Here, we present comprehensive online database ( https://swemacrocycledb.com/ ), housing 5638 permeability datapoints 4216 nonpeptidic macrocycles, curated from literature, patents, bioactivity repositories. addition, descriptor, “amide ratio” (AR), that quantifies peptidic nature macrocyclic compounds, classification peptidic, semipeptidic, macrocycles. Overall, this resource fills gap among existing databases, offering valuable insights into semipeptidic facilitating drug discovery projects.

Language: Английский

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