Interplay among conformation, intramolecular hydrogen bonds, and chameleonicity in the membrane permeability and cyclophilin A binding of Mmacrocyclic peptide cyclosporin O derivatives

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Title
Interplay among conformation, intramolecular hydrogen bonds, and chameleonicity in the membrane permeability and cyclophilin A binding of Mmacrocyclic peptide cyclosporin O derivatives
Author(s)
D Lee; S Lee; J Choi; Y K Song; Min Ju Kim; D S Shin; M A Bae; Y C Kim; C J Park; Kyeong-Ryoon Lee; J H Choi; J Seo
Bibliographic Citation
Journal of Medicinal Chemistry, vol. 64, no. 12, pp. 8272-8286
Publication Year
2021
Abstract
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.
ISSN
0022-2623
Publisher
Amer Chem Soc
DOI
http://dx.doi.org/10.1021/acs.jmedchem.1c00211
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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