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제128회 대한화학회 학술발표회, 총회 및 기기전시회 Effect of molecular chameleonicity on the membrane permeability of macrocyclic peptide cyclosporin O derivatives

등록일
2021년 8월 19일 15시 04분 56초
접수번호
3480
발표코드
ORGN3-2 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
발표시간
금 14시 : 55분
발표형식
심포지엄
발표분야
Organic Chemistry - Current Trends in Chemical Biology and Bioorganic Chemistry
저자 및
공동저자
Jiwon Seo
Chemistry, Gwangju Institute of Science and Technology, Korea
Macrocyclic peptides have emerged as a promising modality to inhibit intracellular protein-protein interactions (PPIs). Membrane permeability is a key factor to the pharmaceutical utility of the macrocyclic peptides providing access to the intracellular target and favorable pharmacokinetic profile. Along with various physico-chemical profiles, a ‘chameleonic’ ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes, is considered as a unique property of certain oral macrocyclic drugs (e.g., cyclosporin A or CsA). To facilitate the usage of this class of macrocycles, a molecular scaffold with well-established structure-property relationship (SPR) is desirable. Here, we adopted cyclosporin O (CsO) as a synthetically accessible scaffold, prepared a library of CsO derivatives, and evaluated their structural characteristics and membrane permeability. Their conformations were characterized by NMR spectroscopy and calculated via molecular simulations with NMR constraints. In a lipophilic environment, CsA and CsO derivatives showed closed conformations, but in polar media, CsO derivatives exhibited a varying degree of chameleonicity depending on their side chain substitutions. Some of the CsO derivatives showed membrane permeability greater than CsA, as determined by the parallel artificial membrane permeability (PAMPA) and Caco-2 assay, and general structural aspect for greater chameleonicity and membrane permeability will be discussed. Our study helps in the understanding of CsO, a macrocyclic peptide less explored than CsA but with more potential for diversity generation, which has led to designable macrocyclic peptides with desirable permeability and biological functions.

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