Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives

A macrocyclic
peptide scaffold with well-established structure–property
relationship is desirable for tackling undruggable targets. Here,
we adopted a natural macrocycle, cyclosporin O (CsO)
and its derivatives (CP1–3), and
evaluated the impact of conformation on membrane permeability, cyclophilin
A (CypA) binding, and the pharmacokinetic (PK) profile. In nonpolar
media, CsO showed a similar conformation to cyclosporin
A (CsA), a well-known chameleonic macrocycle, but less
chameleonic behavior in a polar environment. The weak chameleonicity
of CsO resulted in decreased membrane permeability; however,
the more rigid conformation of CsO was not detrimental
to its PK profile. CsO exhibited a higher plasma concentration
than CsA, which resulted from minimal CypA binding and
lower accumulation in red blood cells and moderate oral bioavailability
(F = 12%). Our study aids understanding of CsO, a macrocyclic peptide that is less explored than CsA but with greater potential for diversity generation and
rational design.

具备明确构效关系（structure–property relationship）的大环肽骨架（macrocyclic peptide scaffold），是攻克不可成药靶点的理想选择。本研究选取天然大环化合物环孢菌素O（cyclosporin O, CsO）及其衍生物（CP1–3），评估了构象对膜通透性（membrane permeability）、亲环蛋白A（cyclophilin A, CypA）结合活性以及药代动力学（pharmacokinetic, PK）特征的影响。在非极性介质中，CsO的构象与知名的变色龙型大环化合物环孢菌素A（cyclosporin A, CsA）相近，但在极性环境中其变色龙性（chameleonicity）较弱。CsO较弱的变色龙性导致其膜通透性下降；然而，CsO更为刚性的构象并未对其药代动力学特征产生不利影响。CsO的血浆浓度高于CsA，这一现象源于其与CypA的结合能力极弱，且在红细胞（red blood cells）中的蓄积量更低，同时其口服生物利用度（oral bioavailability）适中（F=12%）。本研究有助于加深对CsO的理解：相较于CsA，这类大环肽尚未得到充分研究，但在多样性构建（diversity generation）与合理设计（rational design）方面具备更大潜力。