A cell-penetrating helical peptide as a potential HIV-1 inhibitor.

摘要: The capsid domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein is a critical determinant assembly, and therefore potential target for developing drugs AIDS therapy. Recently, 12-mer α-helical peptide (CAI) was reported to disrupt immature- mature-like particle assembly in vitro; however, it failed inhibit HIV-1 cell culture due its inability penetrate cells. same group X-ray crystal structure CAI complex with C-terminal (C-CA) at resolution 1.7 A. Using this structural information, we have utilized structure-based rational design approach stabilize convert cell-penetrating (CPP). modified (NYAD-1) showed enhanced α-helicity. Experiments laser scanning confocal microscopy indicated that NYAD-1 penetrated cells colocalized during trafficking plasma membrane where takes place. disrupted both particles cell-free cell-based vitro systems. NMR chemical shift perturbation analysis mapped binding site residues 169-191 encompassing hydrophobic cavity dimerization an improved affinity over CAI. Furthermore, experimental data indicate most likely targets post-entry stage. Most significantly, inhibited large panel isolates low micromolar potency. Our study demonstrates how strategy can be used cell-impermeable cell-permeable displays activity assays without compromising mechanism action. This proof-of-concept may aid validation as anti-HIV-1 drug help designing peptidomimetics small molecule targeted protein.