Biomedical subjects
Publications and source records attributed to Luc Demange.
Peptide aldehydes are interesting targets as enzyme inhibitors, and can be used for pseudopeptide chemistry or ligation. However, they are known to be subjected to epimerization during synthesis or purification. By (1)H NMR, a model dipeptide aldehyde can be used to check the possible epimerization occurring during synthesis. Various purification methods were investigated, but none was free from epimerization.
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The human cyclophilin hCyp-18, an abundant peptidyl-prolyl cis-trans isomerase (PPIase) implicated in protein folding, controls the infection of CD4(+) T-cells by HIV-1, the pathologic agent of AIDS. Therefore, hCyp-18 is an interesting target for the development of novel anti-HIV-1 therapeutics. We focused on the design of transition-state analogue inhibitors of the PPIase activity of cyclophilin. Most experimental results reported in the literature suggest that hCyp-18 catalyzes the pyramidalization of the nitrogen of pyrrolidine via an H-bond network which results in the deconjugation of the amino acyl-prolyl peptide bond. We proposed the Glypsi(PO(2)R(1)-N)Pro motif (R = alkyl or H) as a selective transition-state analogue inhibitor of cyclophilin. This motif was inserted in Suc-Ala-Ala-Pro-Phe-pNA, a peptide substrate of hCyp-18. The pseudopeptide Suc-Ala-Glypsi(PO(2)Et-N)Pro-Phe-pNA 1b bound to hCyp-18 (K(d) = 20 +/- 5 microM) and was able to selectively inhibit its PPIase activity (IC(50) = 15 +/- 1 microM) but not hFKBP-12, another important PPIase. Deprotection of the phosphonamidate moiety resulted in a complete lack of inhibition. We previously demonstrated that reduction of the Phe-pNA moiety caused a quantitative reduction of the affinity; however, Suc-Ala-Glypsi(PO(2)Et-N)Pro-Phepsi(CH(2)-NH)pNA 7b still bound and inhibited hCyp-18, suggesting that the Glypsi(PO(2)Et-N)Pro motif plays the major role in the binding to cyclophilin. Consequently, we propose compound 1b as being a novel transition-state mimic inhibitor of hCyp-18.