Emerging drug targets for antiretroviral therapy.
Current targets for antiretroviral therapy (ART) include the viral enzymes reverse transcriptase and protease. The use of a combination of inhibitors targeting these enzymes can reduce viral load for a prolonged period and delay disease progression. However, complications of ART, including the emergence of viruses resistant to current drugs, are driving the development of new antiretroviral agents targeting not only the reverse transcriptase and protease enzymes but novel targets as well. Indeed, enfuvirtide, an inhibitor targeting the viral envelope protein (Env) was recently approved for use in combination therapy in individuals not responding to current antiretroviral regimens. Emerging drug targets for ART include: (i) inhibitors that directly or indirectly target Env; (ii) the HIV enzyme integrase; and (iii) inhibitors of maturation that target the substrate of the protease enzyme. Env mediates entry of HIV into target cells via a multistep process that presents three distinct targets for inhibition by viral and cellular-specific agents. First, attachment of virions to the cell surface via nonspecific interactions and CD4 binding can be blocked by inhibitors that include cyanovirin-N, cyclotriazadisulfonamide analogues, PRO 2000, TNX 355 and PRO 542. In addition, BMS 806 can block CD4-induced conformational changes. Secondly, Env interactions with the co-receptor molecules can be targeted by CCR5 antagonists including SCH-D, maraviroc (UK 427857) and aplaviroc (GW 873140), and the CXCR4 antagonist AMD 070. Thirdly, fusion of viral and cellular membranes can be inhibited by peptides such as enfuvirtide and tifuvirtide (T 1249). The development of entry inhibitors has been rapid, with an increasing number entering clinical trials. Moreover, some entry inhibitors are also being evaluated as candidate microbicides to prevent mucosal transmission of HIV. The integrase enzyme facilitates the integration of viral DNA into the host cell genome. The uniqueness and specificity of this reaction makes integrase an attractive drug target. However, integrase inhibitors have been slow to reach clinical development, although recent contenders, including L 870810, show promise. Inhibitors that target viral maturation via a unique mode of action, such as PA 457, also have potential. In addition, recent advances in our understanding of cellular pathways involved in the life cycle of HIV have also identified novel targets that may have potential for future antiretroviral intervention, including interactions between the cellular proteins APOBEC3G and TSG101, and the viral proteins Vif and p6, respectively. In summary, a number of antiretroviral agents in development make HIV entry, integration and maturation emerging drug targets. A multifaceted approach to ART, using combinations of inhibitors that target different steps of the viral life cycle, has the best potential for long-term control of HIV infection. Furthermore, the development of microbicides targeting HIV holds promise for reducing HIV transmission events.
Reeves
Jacqueline D
JD
Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jreeves@mail.med.upenn.edu
Piefer
Andrew J
AJ
D000071478:APOBEC Deaminases; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D000090103:Antiviral Restriction Factors; D001287:Attachment Sites, Microbiological / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000235:genetics; D024882:Drug Resistance, Viral / Q000502:physiology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism*; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism*; D015728:Receptors, HIV / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014759:Viral Envelope Proteins / Q000378:metabolism*
D044966:Anti-Retroviral Agents; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D023581:HIV Fusion Inhibitors; D015728:Receptors, HIV; D000070584:Tripartite Motif Proteins; D014759:Viral Envelope Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D019426:Integrases; D010447:Peptide Hydrolases; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase