Enhancement of Anti-HIV-1 Activity by Hot Spot Evolution of RANTES-Derived Peptides

SummaryCCR5, the major HIV-1 coreceptor, is a primary target for HIV-1 entry inhibition strategies. CCL5/RANTES, a natural CCR5 ligand, is one of the most potent HIV-1 entry inhibitors and, therefore, an ideal candidate to derive HIV-1 blockers. Peptides spanning the RANTES N-loop/β1-strand region act as specific CCR5 antagonists, with their hydrophobic N- and C termini playing a crucial role in virus blockade. Here, hydrophobic surfaces were enhanced by tryptophan substitution of aromatic residues, highlighting position 27 as a critical hot spot for HIV-1 blockade. In a further molecular evolution step, C-terminal engraftment of RANTES 40′ loop produced a peptide with the highest solubility and anti-HIV-1 activity. These modified peptides represent leads for the development of effective HIV-1 inhibitors and microbicides.

► Peptides encompassing CCL5 and CCL4 N-loop/β1-strand region block HIV-1 entry
► Engraftment of 40′ loop in CCL5 peptides increases antiviral activity
► Hydrophobic surface increase at position 27 leads to higher anti-HIV-1 activity
► CCL5-derived peptides act as CCR5 antagonists