Cyclic Peptides for Drug Development

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 63(3)

Published: Oct. 23, 2023

Abstract Cyclic peptides are fascinating molecules abundantly found in nature and exploited as molecular format for drug development well other applications, ranging from research tools to food additives. Advances peptide technologies made over many years through improved methods synthesis have resulted a steady stream of new drugs, with an average around one cyclic approved per year. Powerful screening random libraries, de novo generating ligands, enabled the drugs independent naturally derived now offer virtually unlimited opportunities. In this review, we feature therapeutically relevant discuss unique properties peptides, enormous technological advances ligand recent years, current challenges opportunities developing that address unmet medical needs.

Language: Английский

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Peptidomimetics: An Overview of Recent Medicinal Chemistry Efforts toward the Discovery of Novel Small Molecule Inhibitors

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7438 - 7475

Published: May 23, 2022

The use of peptides as therapeutics has often been associated with several drawbacks such poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications native the aim obtaining molecules that more suitable for clinical development and, this reason, widely used tools in medicinal chemistry programs. effort disclose innovative peptidomimetic therapies is recurrent constantly evolving demonstrated new lead compounds trials. Synthetic strategies peptidomimetics have also implemented time. This perspective highlights some most recent efforts design synthesis agents together their biological evaluation toward a panel targets.

Language: Английский

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Overcoming the Shortcomings of Peptide-Based Therapeutics

Future Drug Discovery, Journal Year: 2022, Volume and Issue: 4(2)

Published: June 1, 2022

Peptides have traditionally been perceived as poor drug candidates due to unfavorable characteristics mainly regarding their pharmacokinetic behavior, including plasma stability, membrane permeability and circulation half-life. Nonetheless, in recent years, general strategies tackle those shortcomings established, peptides are subsequently gaining increasing interest drugs unique ability combine the advantages of antibodies small molecules. Macrocyclic a special focus development efforts address so called ‘undruggable’ targets characterized by large flat protein surfaces lacking binding pockets. Here, main developed date for adapting clinical use summarized, which may soon help usher an age highly shaped peptide-based therapeutics. limited is still overcome before peptide therapeutics will be broadly accepted.

Language: Английский

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Cyclic Peptides in Pipeline: What Future for These Great Molecules?

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(7), P. 996 - 996

Published: July 12, 2023

Cyclic peptides are molecules that already used as drugs in therapies approved for various pharmacological activities, example, antibiotics, antifungals, anticancer, and immunosuppressants. Interest these has been growing due to the improved pharmacokinetic pharmacodynamic properties of cyclic structure over linear by evolution chemical synthesis, computational, vitro methods. To date, 53 have different regulatory authorities, many others clinical trials a wide diversity conditions. In this review, potential is presented, general aspects their synthesis development discussed. Furthermore, an overview also given, summarized.

Language: Английский

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Ynamide Coupling Reagents: Origin and Advances

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: 57(6), P. 855 - 869

Published: March 7, 2024

ConspectusSince the pioneering work of Curtius and Fischer, chemical peptide synthesis has witnessed a century's development evolved into routine technology. However, it is far from perfect. In particular, challenged by sustainable because state-of-the-art heavily relies on legacy reagents technologies developed before establishment green chemistry. Over past three decades, broad range efforts have been made for greening synthesis, among which using unprotected amino acid represents an ideal promising strategy does not require protection deprotection steps. Unfortunately, C → N employing acids plagued undesired polymerization, while inverse with retarded severe racemization/epimerization owing to iterative activation aminolysis high susceptible peptidyl acids. Consequently, there urgent need develop innovative coupling strategies novel mechanisms that can address long-standing notorious issue synthesis.This Account will describe our in discovery ynamide their application synthesis. eight-year journey, class general both amide ester bond formation. superiority suppressing enabled them be effective fragment condensation, head-to-tail cyclization, as well precise incorporation thioamide substitutions backbones. The first practical was successfully accomplished harnessing such features taking advantage transient strategy. Ynamide reagent-mediated formation efficient intermolecular esterification macrolactonization preservation α-chirality configuration conjugated α,β-C–C double bond. To make readily available reasonable cost convenience, we scalable one-step synthetic method cheap starting materials. Furthermore, water-removable reagent developed, offering column-free purification target product. addition, recycle accomplished, thereby paving way industrial application.As such, this presents whole story origin, mechanistic insights, preparation, applications, perspective highlights future impact

Language: Английский

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Nickel-mediated aerobic C(sp2)–nucleophile coupling reactions for late-stage diversification of aryl electrophiles

Nature Synthesis, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Language: Английский

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On the Utility of Chemical Strategies to Improve Peptide Gut Stability

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(8), P. 6191 - 6206

Published: April 14, 2022

Inherent susceptibility of peptides to enzymatic degradation in the gastrointestinal tract is a key bottleneck oral peptide drug development. Here, we present systematic analysis (i) gut stability disulfide-rich scaffolds, orally administered therapeutics, and well-known neuropeptides (ii) medicinal chemistry strategies improve stability. Among broad range studied peptides, cyclotides were only scaffold class resist degradation, even when grafted with non-native sequences. Backbone cyclization, frequently applied strategy, failed intestinal fluid, but several site-specific alterations proved efficient. This work furthermore highlights importance standardized test conditions suggests defined protocols facilitate cross-study comparison. Together, our results provide comparative overview framework for chemical engineering gut-stable which should be valuable development therapeutics molecular probes targeting receptors within tract.

Language: Английский

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Targeting Peptides: The New Generation of Targeted Drug Delivery Systems

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(6), P. 1648 - 1648

Published: June 3, 2023

Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production stability physiological environments; recent years, they have been increasingly studied agents for several diseases, from tumors central nervous system disorders, also thanks the ability some them cross blood–brain barrier. In this review, we will describe techniques employed their experimental silico design, well possible applications. We discuss advancements formulation chemical modifications that make even more stable effective. Finally, how use could effectively help overcome various problems improve existing treatments.

Language: Английский

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A Cysteine‐Directed Proximity‐Driven Crosslinking Method for Native Peptide Bicyclization

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(31)

Published: June 7, 2023

Efficient and site-specific modification of native peptides proteins is desirable for synthesizing antibody-drug conjugates as well constructing chemically modified peptide libraries using genetically encoded platforms such phage display. In particular, there much interest in efficient multicyclization due to the appeals multicyclic therapeutics. However, conventional approaches synthesis require orthogonal protecting groups or non-proteinogenic clickable handles. Herein, we report a cysteine-directed proximity-driven strategy bicyclic from simple natural precursors. This linear bicycle transformation initiates with rapid cysteine labeling, which then triggers amine-selective cyclization. bicyclization proceeds rapidly under physiologic conditions, yielding Cys-Lys-Cys, Lys-Cys-Lys N-terminus-Cys-Cys stapling pattern. We demonstrate utility power this by fused M13 phage, paving way display novel libraries.

Language: Английский

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Evolution of Pyrrolysyl-tRNA Synthetase: From Methanogenesis to Genetic Code Expansion

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(16), P. 9580 - 9608

Published: July 2, 2024

Over 20 years ago, the pyrrolysine encoding translation system was discovered in specific archaea. Our Review provides an overview of how once obscure pyrrolysyl-tRNA synthetase (PylRS) tRNA pair, originally responsible for accurately translating enzymes crucial methanogenic metabolic pathways, laid foundation burgeoning field genetic code expansion. primary focus is discussion to successfully engineer PylRS recognize new substrates and exhibit higher

Language: Английский

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