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|
| Type |
Poster Presentation |
| Area |
Life Chemistry |
| Room No. |
Exhibition Hall 2 |
| Time |
4월 19일 (금요일) 11:00~12:30 |
| Code |
LIFE.P-379 |
| Subject |
Synthesis and structural investigation of cyclosporin O derivatives and its structure-permeability relationship (SPR) study |
| Authors |
Dongjae Lee, Jiwon Seo*
Department of Chemistry, Gwangju Institute of Science and Technology, Korea
|
| Abstract |
As inspired by cyclosporin A (CsA) which was well known natural cyclic peptide with highly oral bioavailability, cyclic peptides have been widely discussed as a promising macrocyclic scaffold which possessed high permeability with large surface area and constrained conformation. Recently, unique structural features (e.g., N-methylation) and conformational changes depending on environmental polarity (chameleonicity) make cyclic peptides permeable was reported. In cyclosporine family, cyclosporin O (CsO) is a unique member in the absence of MeBmt residue which caused non-specific cyclophillin-binding and synthetic difficulty was adopted as a basic scaffold to design CsO derivatives. CsO and its derivatives were synthesized, and their structural investigation was carried out via NMR spectroscopy, computational calculation containing molecular dynamics and quantum mechanics. CsO exhibited transannular interactions as shown in CsA, while CsO derivatives demonstrated a modulated rigidity depending on specific substitutions. In addition, strength and exposure index toward solvent of hydrogen bonds were investigated to evaluate the conformational changes by environmental polarity. Under structural understanding, PAMPA and caco-2 permeability assay were carried out to investigate a structure-permeability relationship (SPR) of CsO derivatives. This study will provide a rationale design of cyclic peptides with more permeable and predictable physico-chemical properties. |
| E-mail |
ldj@gist.ac.kr |
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123rd General Meeting of the KCS