Journal
PROTEIN ENGINEERING DESIGN & SELECTION
Volume 21, Issue 2, Pages 65-72Publisher
OXFORD UNIV PRESS
DOI: 10.1093/protein/gzm079
Keywords
CCR5; HIV coreceptor; MIP-1 beta CCL4; pharmacophore grafting; PSC-RANTES
Funding
- NIAID NIH HHS [P01 AI 51649-01] Funding Source: Medline
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The HIV coreceptor CCR5 is a validated target for both the prevention and therapy of HIV infection. PSC-RANTES, an N-terminally modified analogue of one of the natural chemokine ligands of CCR5 (RANTES/CCL5), is a potent inhibitor of HIV entry into target cells. Here, we set out to engineer the anti-HIV activity of PSC-RANTES into another natural CCR5 ligand (MIP-1 beta/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1 beta/CCL4 analogues that retain the receptor binding profile of MIP-1 beta/CCL4, but acquire the very high anti-HIV potency and characteristic inhibitory mechanism of PSC-RANTES. Unexpectedly, we discovered that in addition to N-terminal structures from PSC-RANTES, the side chain of Lys(33) is also necessary for full anti-HIV potency.
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