The current status of the NNRTI family of antiretrovirals used in the HAART regime against HIV infection.
Acquired immunodeficiency syndrome (AIDS) remains, after 25 years of its discovery, as one of the major threats to human life. Reverse Transcriptase is an essential enzyme for virus replication, and therefore constitutes a major target in HIV-1 therapy. Among the different types of drugs targeting RT, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) act by binding in an induced-fit allosteric pocket. In this review, we explore the several NNRTIs' structures and binding interactions, as well as their mechanisms of action. The conformational changes that they cause in RT and their effects on the topology of the active site are discussed. The emergence of mutant, resistant viruses is analysed, focussing on the mutations responsible for the loss of antiviral efficacy of NNRTIs. Explanations for the role of those mutations are presented. Emergent drugs in the pipeline, together with the underlying strategies for drug development, are also analysed.
Martins
Sílvia
S
Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.
Ramos
Maria João
MJ
Fernandes
Pedro Alexandrino
PA
D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites; D002986:Clinical Trials as Topic; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000145:classification / Q000627:therapeutic use*
D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase