Nucleoside RT Inhibitors: Structural and Molecular Biology

  • Gaofei Lu
  • Antonio J. Acosta-Hoyos
  • Walter A. Scott
Chapter

Abstract

Nucleoside analogs were the earliest drugs developed to combat HIV-1 infection. These drugs are taken up by cellular transport systems, activated by cellular kinases, and incorporated into DNA by HIV-1 reverse transcriptase (RT) during the initial stages of viral infection, leading to termination of viral DNA synthesis. This class of anti-HIV drugs has now grown to eight FDA- approved compounds with several more potential drugs in development. Biochemical studies of DNA synthesis by HIV-1 RT and determination of three-dimensional structures of nucleoprotein complexes containing HIV-1 RT have shed light on how changes in enzyme structure can lead to drug resistance. A challenge to developing nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs) is the construction of compounds that will enter cells efficiently and be efficiently converted into the active form of the inhibitor. The intracellular concentrations of the activated drug metabolites and the natural dNTPs are important parts of the equation that determines antiviral activity. The intracellular environments where nucleotide incorporation occurs and where repair of damaged or chain-terminated viral DNA occurs are not well defined and represent a remaining frontier in the further development of drugs that target the dNTP binding site of HIV-1 RT.

Keywords

Adenine Thymidine Cytosine Triphosphate Hydrolase 

Notes

Acknowledgments

G.L. and A. J. A-H were supported by predoctoral fellowships from the American Heart Association (2280106 and 0615079B). This work was supported by the US Public Health Service grant AI-39973 to W.A.S. and the University of Miami Developmental Center for AIDS Research (P30-AI-073961).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gaofei Lu
    • 1
  • Antonio J. Acosta-Hoyos
    • 2
  • Walter A. Scott
    • 1
  1. 1.Department of Biochemistry & Molecular BiologyUniversity of Miami Miller School of MedicineMiamiUSA
  2. 2.Medicina, Universidad Simón BolívarBarranquilla, AtlanticoColombia

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