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.