End-to-End Backbone Cyclization Enhances Passive Permeability of bRo5 Oligomeric Depsipeptides with Nonlinear Size Dependence.

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-03-20 eCollection Date: 2025-04-10 DOI:10.1021/acsmedchemlett.5c00037

Madelaine P Thorpe, Corey R Hopkins, Jeffrey N Johnston

引用次数: 0

Abstract

A majority of drugs are small molecules that satisfy Lipinski's Rule-of-Five (Ro5), but efforts to target topologically complex biomolecular interactions have reignited interest in nonconforming molecular therapeutics, dubbed "beyond Ro5 (bRo5)". Broadly useful design principles for bRo5 molecules are few in number, although several studies have highlighted the benefit to bioavailability and proteolytic stability that can result from the introduction of a constraining ring into conformationally mobile peptides. Here we show that a linear oligomeric depsipeptide (OD) template can be leveraged to link size to permeability, while the corresponding cyclic oligomeric depsipeptide (COD) series is used to determine the impact of cyclization as an added conformational constraint. Unexpectedly, certain macrocycle sizes confer a greater benefit to permeability than others.

查看原文本刊更多论文

端到端主链环化增强具有非线性尺寸依赖性的bRo5寡聚沉积肽的被动渗透性。

大多数药物都是满足利平斯基五规则（Ro5）的小分子，但针对拓扑复杂的生物分子相互作用的努力重新点燃了对不符合规则的分子治疗的兴趣，被称为“超越Ro5 （bRo5）”。广泛适用于bRo5分子的设计原则数量很少，尽管一些研究强调了在构象可移动的肽中引入约束环对生物利用度和蛋白水解稳定性的好处。在这里，我们展示了一个线性寡聚沉积肽（OD）模板可以用来连接大小和渗透率，而相应的环寡聚沉积肽（COD）系列被用来确定环化的影响，作为一个额外的构象约束。出乎意料的是，某些大循环尺寸比其他尺寸更有利于渗透率。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.