Synthesis and Evaluation of Glyψ(PO2R-N)Pro-Containing Pseudopeptides as Novel Inhibitors of the Human Cyclophilin hCyp-18

• Published in: Journal of medicinal chemistry Vol. 45; no. 18; pp. 3928 - 3933
• Main Authors: Demange, Luc, Moutiez, Mireille, Dugave, Christophe
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29-08-2002
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Chemical Sciences; Life Sciences; Medical sciences; Organic chemistry; Pharmacology. Drug treatments; Human; Peptidylprolyl isomerase; Peptides; HIV-1 virus; Enzyme; Tripeptide; Retroviridae; Enzyme inhibitor; Selectivity; Lentivirus; In vitro; Phosphorus Organic compounds; Pseudopeptide; Virus; Organic amidophosphonate; Isomerases; Structure activity relation; Transition state; Antiviral; Peptide synthesis; Human immunodeficiency virus; Inhibition; Chemical synthesis; cis-trans-Isomerases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020865i

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 Glyψ(PO2R-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-Glyψ(PO2Et-N)Pro-Phe-pNA 1b bound to hCyp-18 (K d = 20 ± 5 μM) and was able to selectively inhibit its PPIase activity (IC50 = 15 ± 1 μM) 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-Glyψ(PO2Et-N)Pro-Pheψ(CH2-NH)pNA 7b still bound and inhibited hCyp-18, suggesting that the Glyψ(PO2Et−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.