较大的无环β-发夹肽的被动膜通透性
Passive Membrane Permeability of Sizable Acyclic β-Hairpin Peptides.
作者信息
Moxam Jillene, Naylon Sarah, Richaud Alexis D, Zhao Guangkuan, Padilla Alberto, Roche Stéphane P
机构信息
Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, Florida 33431, United States.
Department of Natural Science, Keiser University, Fort Lauderdale, Florida 33309, United States.
出版信息
ACS Med Chem Lett. 2023 Jan 27;14(3):278-284. doi: 10.1021/acsmedchemlett.2c00486. eCollection 2023 Mar 9.
Abstract
The recent shift toward increasingly larger drug modalities has created a significant demand for novel classes of compounds with high membrane permeability that can inhibit intracellular protein-protein interactions (PPIs). While major advances have been made in the design of cell-permeable helices, stapled β-sheets, and cyclic peptides, the development of large acyclic β-hairpins lags far behind. Therefore, we investigated a series of 26 β-hairpins (MW > 1.6 kDa) belonging to a chemical space the Lipinski "rule of five" (Ro5) and showed that, in addition to their innate plasticity, the lipophilicity of these peptides (log ≈ 0 ± 0.7) can be tuned to drastically improve the balance between aqueous solubility and passive membrane permeability.
摘要
最近向越来越大的药物形式的转变，对具有高膜通透性、能抑制细胞内蛋白质-蛋白质相互作用（PPI）的新型化合物产生了巨大需求。虽然在可穿透细胞的螺旋、订书钉状β折叠片和环肽的设计方面取得了重大进展，但大型无环β发夹的开发却远远滞后。因此，我们研究了一系列26种β发夹（分子量>1.6 kDa），它们属于一个化学空间——Lipinski“五规则”（Ro5），结果表明，除了其固有的可塑性外，这些肽的亲脂性（log ≈ 0 ± 0.7）可以进行调节，以大幅改善水溶性和被动膜通透性之间的平衡。
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