Design of a gag pentapeptide analogue that binds human cyclophilin A more efficiently than the entire capsid protein: new insights for the development of novel Anti-HIV-1 drugs - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2000

Design of a gag pentapeptide analogue that binds human cyclophilin A more efficiently than the entire capsid protein: new insights for the development of novel Anti-HIV-1 drugs

Résumé

Cyclophilin A (hCyp-18), a ubiquitous cytoplasmic peptidyl-prolyl cis/trans isomerase (PPIase), orchestrates HIV-1 core packaging. hCyp-18, incorporated into the virion, enables core uncoating and RNA release and consequently plays a critical role in the viral replication process. hCyp18 specifically interacts with a single exposed loop of the Gag polyprotein capsid domain via a network of nine hydrogen bonds which mainly implicates a 7-mer fragment of the loop. As previously reported, the corresponding linear heptapeptide Ac-Val-His-Ala-Gly-Pro-Ile-AlaNH$_2$ binds to hCyp-18 with a low affinity (IC$_{50}$)= 850 $\pm 220 µM but a potentially useful selectivity for hCyp-18 relative to hFKBP-12, another abundant PPIase. On the basis of X-ray structures of Gag fragments:hCyp-18 complexes, we generated a series of modified peptides in order to probe the determinants of the interaction and hence to select a peptidic ligand displaying a higher affinity than the capsid domain of Gag. We synthesized a series of heptapeptides to test the energetic contribution of amino acids besides the Gly-Pro moiety. In particular the importance of the histidine residue for the interaction was underscored. We also investigated the influence of N- and C-terminal modifications. Hexapeptides containing either deaminovaline (Dav) in place of the N-terminal valine or substitution of the C-terminal alanine amide with a benzylamide group displayed increased affinities. Combination of both modifications gave the most potent competitor Dav-His-Ala-Gly-Pro-Ile-NHBn which has a higher affinity for hCyp-18 (K$_d$ ) 3 ( 0.5 µM) than the entire capsid protein (K$_d$ = 16 $\pm$ 4 µM) and a very low affinity for hFKBP-12. Some of our results strongly suggest that the title compound is not a substrate of hCyp-18 and interacts preferentially in the trans conformation.

Dates et versions

hal-03637514 , version 1 (11-04-2022)

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Citer

Quan Li, Mireille Moutiez, Jean-Baptiste Charbonnier, Karine Vaudry, André Ménez, et al.. Design of a gag pentapeptide analogue that binds human cyclophilin A more efficiently than the entire capsid protein: new insights for the development of novel Anti-HIV-1 drugs. Journal of Medicinal Chemistry, 2000, 43 (9), pp.1770-1779. ⟨10.1021/jm9903139⟩. ⟨hal-03637514⟩
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