An update in the development of HIV entry inhibitors.
HIV entry and fusion are two steps in the viral life cycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and to the various steps of such processes which are subject to interactions with small molecules. Intense research led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120-CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Recently, a third family of antivirals started to be used clinically (in addition to the reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, offering thus the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently investigated in controlled clinical trials, and there are a number of them that is bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating adherence of patients to these medications and preventing the development of drug resistance.
Rusconi
Stefano
S
Dipartimento di Scienze Cliniche Luigi Sacco, Cattedra di Malattie Infettive e Tropicali, Università degli Studi, Ospedale Luigi Sacco, Milano, Italy.
Scozzafava
Andrea
A
Mastrolorenzo
Antonio
A
Supuran
Claudiu T
CT
D018925:Chemokines; D004359:Drug Therapy, Combination; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D018925:Chemokines; D023581:HIV Fusion Inhibitors; D019707:Receptors, Chemokine