Highly potent HIV inhibition:: engineering a key anti-HIV structure from PSC-RANTES into MIP-1β/CCL4

被引：21

作者：

Gaertner, Hubert ^{[1
]}

Lebeau, Olivier ^{[1
]}

Borlat, Irene ^{[1
]}

Cerini, Fabrice ^{[1
]}

Dufour, Brigitte ^{[1
]}

Kuenzi, Gabriel ^{[1
]}

Melotti, Astrid ^{[1
]}

Fish, Richard J. ^{[1
]}

Offord, Robin ^{[1
,3
]}

Springael, Jean-Yves ^{[2
]}

Parmentier, Marc ^{[2
]}

Hartley, Oliver ^{[1
]}

机构：

[1] Ctr Med Univ Geneva, Dept Struct Biol & Bioinformat, CH-1211 Geneva 4, Switzerland

[2] IRIBHM, B-1070 Brussels, Belgium

[3] Mintaka Fdn Med Res, CH-1228 Plan Les Ouates, Switzerland

来源：

PROTEIN ENGINEERING DESIGN & SELECTION | 2008年 / 21卷 / 02期

关键词：

CCR5; HIV coreceptor; MIP-1 beta CCL4; pharmacophore grafting; PSC-RANTES;

D O I：

10.1093/protein/gzm079

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：65 / 72

页数：8

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