[Viral entry as therapeutic target. Current situation of entry inhibitors].
Viral entry is an early stage and specific of the infection in which different viral and cellular targets are accessible to therapeutic treatment. CXCR4 and CCR5 act in this process as coreceptor molecules of HIV for its entry into the host cell. The predominant role played by the CCR5 coreceptor in the transmission and spreading of HIV makes this molecule the target of choice for blocking this mechanism. In the last few years, different specific inhibitors of HIV coreceptors have been generated of which only one, Maraviroc, has been approved for clinical use. The synthetic inhibitors developed act as allosteric antagonists that induce a non-permissive state or configuration of the coreceptor for binding viral envelope-glycoproteins. The CCR5 antagonists act on a wide spectrum of viruses with affinity or tropism for this receptor (virus R5), are absorbed orally and have powerful antiviral activity. However, the optimistic perspective offered by these new molecules has to be moderated due to the possible and expected appearance of viral resistances, on the one hand, and the propagation of viral species with affinity or tropism for the CXCR4 receptor (virus X4). This situation is a reality verified in the first clinical trials with these drugs and they acutely and urgently show the need to have effective and non-toxic CXCR4 inhibitors available to block this alternative viral replication and escape route.
Arenzana-Seisdedos
Fernando
F
Unidad de Patogenia Viral Molecular, Instituto Pasteur, París, Francia. farenzan@pasteur.fr
D000328:Adult; D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000737:chemistry / Q000502:physiology; D019742:Chemokines, CC / Q000502:physiology; D019743:Chemokines, CXC / Q000502:physiology; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054659:Diketopiperazines; D015195:Drug Design; D006678:HIV / Q000502:physiology*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077592:Maraviroc; D008561:Membrane Fusion / Q000187:drug effects*; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000737:chemistry / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D053585:Virus Attachment / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000502:physiology
D000577:Amides; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D019742:Chemokines, CC; D019743:Chemokines, CXC; D003510:Cyclohexanes; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D013141:Spiro Compounds; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; C499671:aplaviroc; C119369:TAK 779; D000077592:Maraviroc; C486781:vicriviroc