Engineering chemokines to develop optimized HIV inhibitors.
Since the discovery that to enter target cells HIV uses receptors for the class of proteins known as chemokines, attempts have been made to generate anti-HIV molecules based on the chemokine ligands. A significant level of knowledge of the structure-activity relationships of chemokines has been amassed since the beginning of the 1990s. This, together with work that has elucidated the mechanisms underlying the inhibitory activity of chemokines, has guided not only the rational design of anti-HIV chemokine analogues, but also strategies by which chemokine variants with potent anti-HIV activity can be isolated from large libraries by phage display. This review summarizes the current knowledge about the structure-activity relationships and receptor biology of chemokines that is relevant to the development of analogues with anti-HIV activity. We present specific examples of engineered chemokine analogues with potent anti-HIV activity and describe the challenges that will need to be faced if these molecules are to be further developed for clinical applications. Finally, we discuss how these challenges might be met through further engineering of the molecules.
Hartley
Oliver
O
Department of Structural Biology and Bioinformatics, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. oliver.hartley@medecine.unige.ch
Offord
Robin E
RE
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D018925:Chemokines / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology* / Q000502:physiology; D015195:Drug Design; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D008958:Models, Molecular; D019151:Peptide Library; D015202:Protein Engineering / Q000379:methods*; D019707:Receptors, Chemokine / Q000502:physiology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D018925:Chemokines; D019151:Peptide Library; D019707:Receptors, Chemokine; C111989:aminooxypentane-RANTES