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PEDS Advance Access originally published online on January 4, 2008
Protein Engineering Design and Selection 2008 21(2):65-72; doi:10.1093/protein/gzm079
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Hubert Gaertner1, Olivier Lebeau1, Irène Borlat1, Fabrice Cerini1, Brigitte Dufour1, Gabriel Kuenzi1, Astrid Melotti1, Richard J. Fish1,4, Robin Offord1,3, Jean-Yves Springael2, Marc Parmentier2 and Oliver Hartley1,5

1Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland 2 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), ULB Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium 3Mintaka Foundation for Medical Research, 14 chemin des Aulx, 1228 Plan-les Ouates, Switzerland

5 To whom correspondence should be addressed. E-mail: oliver.hartley{at}medecine.unige.ch

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 Lys33 is also necessary for full anti-HIV potency.

Keywords: CCR5/HIV coreceptor/MIP-1β CCL4/pharmacophore grafting/PSC-RANTES

Received July 12, 2007; revised October 3, 2007; accepted November 4, 2007.

4 Present address: Service of Angiology and Hemostasis, Department of Internal Medicine, Geneva University Hospital, 24, rue Micheli-du Crest, 1211 Geneva 4, Switzerland


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