Synthesis and evaluation of Glypsi(PO(2)R-N)Pro-containing pseudopeptides as novel inhibitors of the human cyclophilin hCyp-18.

Abstract

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.

• Authors: Luc Demange, Mireille Moutiez, Christophe Dugave
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 45 Issue 18 Pg. 3928-33 (Aug 29 2002) ISSN: 0022-2623 [Print] United States
• PMID: 12190314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Enzyme Inhibitors
• Oligopeptides
• Organophosphonates
• cyclophilin hCyp-18
• succinyl-alanyl-glycyl-pseudo(PO2Et-N)prolyl-phenylalanine-4-nitroaniline
• Cyclophilins

Topics

• Amides (chemistry)
• Cyclophilins (antagonists & inhibitors, chemistry)
• Enzyme Inhibitors (chemical synthesis, chemistry)
• Humans
• Molecular Mimicry
• Oligopeptides (chemical synthesis, chemistry)
• Organophosphonates (chemistry)