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Title

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

Authors
Lebeau, Olivier
Borlat, Irène
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Published in Protein Engineering, Design and Selection. 2008, vol. 21, no. 2, p. 65-72
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-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.
Keywords Amino Acid SequenceAnti-HIV Agents/chemical synthesisCells CulturedChemokine CCL4/genetics/therapeutic useChemokine CCL5/genetics/therapeutic useDrug DesignHIV/drug effectsHumansMolecular Sequence DataStructure-Activity Relationship
Identifiers
PMID: 18178567
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Structures
Research groups Endothélium vasculaire (11)
Bases moléculaires des anomalies génétiques de l'hémostase (504)
HIV (835)
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(ISO format)
GAERTNER, Hubert Francois et al. Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1 beta/CCL4. In: Protein Engineering, Design and Selection, 2008, vol. 21, n° 2, p. 65-72. https://archive-ouverte.unige.ch/unige:815

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Deposited on : 2009-02-16

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