Gaertner Hubert, Lebeau Olivier, Borlat Irène, Cerini Fabrice, Dufour Brigitte, Kuenzi Gabriel, Melotti Astrid, Fish Richard J, Offord Robin, Springael Jean-Yves, Parmentier Marc, Hartley Oliver
Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
Protein Eng Des Sel. 2008 Feb;21(2):65-72. doi: 10.1093/protein/gzm079. Epub 2008 Jan 4.
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-1beta/CCL4), by grafting into it the key N-terminal pharmacophore region from PSC-RANTES. We were able to identify MIP-1beta/CCL4 analogues that retain the receptor binding profile of MIP-1beta/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 Lys33 is also necessary for full anti-HIV potency.
HIV共受体CCR5是HIV感染预防和治疗的一个经过验证的靶点。PSC-RANTES是CCR5天然趋化因子配体之一（RANTES/CCL5）的N端修饰类似物，是HIV进入靶细胞的有效抑制剂。在此，我们着手通过将PSC-RANTES的关键N端药效团区域嫁接到另一种天然CCR5配体（MIP-1β/CCL4）中，来改造PSC-RANTES的抗HIV活性。我们能够鉴定出保留MIP-1β/CCL4受体结合特征，但获得PSC-RANTES非常高的抗HIV效力和特征性抑制机制的MIP-1β/CCL4类似物。出乎意料的是，我们发现除了PSC-RANTES的N端结构外，Lys33的侧链对于完全抗HIV效力也是必需的。
