학술논문
Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1β/CCL4
Document Type
Academic Journal
Author
Source
Protein Engineering, Design and Selection. Feb 01, 2008 21(2):65-72
Subject
Language
English
ISSN
1741-0126
Abstract
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-1β/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1β/CCL4 analogues that retain the receptor binding profile of MIP-1β/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 is also necessary for full anti-HIV potency.