Thorpe Madelaine P, Hopkins Corey R, Johnston Jeffrey N
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
ACS Med Chem Lett. 2025 Mar 20;16(4):638-645. doi: 10.1021/acsmedchemlett.5c00037. eCollection 2025 Apr 10.
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.
大多数药物是符合Lipinski五规则（Ro5）的小分子，但针对拓扑复杂生物分子相互作用的研究重新点燃了人们对不符合该规则的分子疗法（即“超越Ro5（bRo5）”）的兴趣。尽管有几项研究强调了在构象可变的肽中引入一个约束环对生物利用度和蛋白水解稳定性的益处，但适用于bRo5分子的通用设计原则却很少。在这里，我们表明可以利用线性寡聚缩肽（OD）模板将大小与渗透性联系起来，而相应的环状寡聚缩肽（COD）系列则用于确定环化作为一种额外的构象约束的影响。出乎意料的是，某些大环尺寸对渗透性的益处比其他尺寸更大。
