Discovery of a potent peptidic cyclophilin A inhibitor Trp-Gly-Pro

Through virtual screening of a rationally built database consisting of 40 peptides, we identified three short peptides. After testing these three synthetic peptides, we found that the peptide Trp-Gly-Pro (WGP) showed comparable inhibitory ability as positive control cyclosporine A (CsA) on CypA-mediated PPIase activity with IC50 values of 33.11 nM and 10.25 nM, respectively. The peptide WGP had same order of CypA-binding affinity as CsA with dissociation equilibrium constant KD of 3.41 × 10−6 and 6.42 × 10−6 M, respectively. This peptide could also inhibit HIV-1IIIB infection. This study provides a novel strategy for rational design and development of peptidic drugs.

Peptidic inhibitor Trp-Gly-Pro binds to the active site of cyclophilin A by hydrophobic interactions and forming multiple hydrogen bonds.Figure optionsDownload as PowerPoint slideHighlights
► Rationally design of a focused peptide library consisting of 40 peptides based on our previous findings.
► Three peptides were identified with the binding energy lower than the positive control CsA.
► WGP, one of the three selected peptides, showed comparable inhibitory ability as CsA on CypA-mediated PPIase activity.
► WGP had same order of CypA-binding affinity as CsA and could also inhibit HIV-1IIIB infection.
► A potent peptidic inhibitor WGP with low molecular size and low cytotoxicity was identified for CypA.