Chemokine receptors as new molecular targets for antiviral therapy.
Extraordinary advancements have been made over the past decade in our understanding of the molecular mechanism of human immunodeficiency virus (HIV) entry into cells. The external HIV envelope glycoprotein, gp120, sequentially interacts with two cellular receptor molecules, the CD4 glycoprotein and a chemokine receptor, such as CCR5 or CXCR4, leading to the activation of the fusogenic domain of the transmembrane viral glycoprotein, gp41, which changes its conformation to create a hairpin structure that eventually triggers fusion between the viral and cellular membranes. Each of these discrete steps in the viral entry process represents a potential target for new antiviral agents. Current efforts to develop safe and effective HlV entry inhibitors are focused on naturally occurring proteins (e.g., chemokines, antibodies), engineered or modified derivatives of natural proteins (e.g., multimerized soluble CD4, gp41--or chemokine--derived synthetic peptides), as well as small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design. The recent introduction in therapy of the first fusion inhibitor, the gp41-derived synthetic peptide T20, heralds a new era in the treatment of AIDS, which will hopefully lead to more effective multi-drug regimens with reduced adverse effects for the patients.
Santoro
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F
Dibit, San Raffaele Scientific Institute, Milano, Italy.
Vassena
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L
Lusso
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P
D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D019713:Receptors, CCR5 / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000187:drug effects; D019707:Receptors, Chemokine / Q000187:drug effects*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D000077560:Enfuvirtide