Highly potent HIV inhibition: engineering a key anti-HIV structure from PSC-RANTES into MIP-1 beta/CCL4.
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.
Gaertner
Hubert
H
Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland.
Lebeau
Olivier
O
Borlat
Irène
I
Cerini
Fabrice
F
Dufour
Brigitte
B
Kuenzi
Gabriel
G
Melotti
Astrid
A
Fish
Richard J
RJ
Offord
Robin
R
Springael
Jean-Yves
JY
Parmentier
Marc
M
Hartley
Oliver
O
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000235:genetics / Q000627:therapeutic use*; D018946:Chemokine CCL5 / Q000235:genetics / Q000627:therapeutic use*; D015195:Drug Design; D006678:HIV / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D054407:Chemokine CCL4; D018946:Chemokine CCL5; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-