Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase

@article{Singh2010StructuralAO,
  title={Structural Aspects of Drug Resistance and Inhibition of HIV-1 Reverse Transcriptase},
  author={Kamalendra Singh and Bruno Marchand and Karen A. Kirby and Eleftherios Michailidis and Stefan G. Sarafianos},
  journal={Viruses},
  year={2010},
  volume={2},
  pages={606 - 638}
}
HIV-1 Reverse Transcriptase (HIV-1 RT) has been the target of numerous approved anti-AIDS drugs that are key components of Highly Active Anti-Retroviral Therapies (HAART). It remains the target of extensive structural studies that continue unabated for almost twenty years. The crystal structures of wild-type or drug-resistant mutant HIV RTs in the unliganded form or in complex with substrates and/or drugs have offered valuable glimpses into the enzyme’s folding and its interactions with DNA and… 
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References

SHOWING 1-10 OF 181 REFERENCES
Designing anti-AIDS drugs targeting the major mechanism of HIV-1 RT resistance to nucleoside analog drugs.
TLDR
There is an urgent need for new drugs and for new therapies that can overcome the excision mechanism of resistance, and detailed understanding of drug resistance mechanisms can reveal novel targets for anti-viral agents.
Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition.
TLDR
A better understanding of the structure and function of RT and of the mechanism(s) of inhibition can be used to generate better drugs; in particular, drugs that are effective against the current drug-resistant strains of HIV-1.
Inhibitors of HIV- I reverse transcriptase
Publisher Summary This chapter discusses the current clinically used reverse transcriptase (RT) inhibitors and some promising new inhibitors still in preclinical development, emphasizing the
Structure of HIV-2 reverse transcriptase at 2.35-Å resolution and the mechanism of resistance to non-nucleoside inhibitors
TLDR
The availability of a refined structure of HIV-2 RT will provide a stimulus for the structure-based design of novel non-nucleoside inhibitors that could be used against HIV- 2 infection.
Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase.
TLDR
Structural studies have contributed to the design of newer generation NNRTIs and identified a number of features which may contribute to their much improved resistance profiles, including reduced interactions with Tyr181, the presence of inhibitor/main-chain H-bonds and ability to undergo conformational flexing and rearrangement within the mutated drug site.
Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase.
TLDR
The excision reaction can be modulated by mutations conferring resistance to nucleoside or nonnucleoside RT inhibitors, and by amino acid substitutions that interfere with the proper binding of the template-primer, including mutations that affect RNase H activity.
The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance.
TLDR
The structural differences between unliganded wild-type and Lys103Asn mutant HIV-1 RT may correspond to stabilization of the closed-pocket form of the enzyme, which could interfere with the ability of inhibitors to bind to the enzyme.
Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors.
TLDR
Modeling the asparagine mutation of lysine 103 shows that a hydrogen bond between it and tyrosine 188 could form as readily in the CP-94,707 complex as it does in the apoenzyme structure, providing an explanation for the activity of this inhibitor against this clinically important mutant.
Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids.
  • S. Sarafianos, K. Das, +4 authors E. Arnold
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
A model is developed that explains the ability of the 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide analog 3TCTP and can also explain the 3 TC resistance of analogous hepatitis B polymerase mutants.
Interaction kinetic characterization of HIV-1 reverse transcriptase non-nucleoside inhibitor resistance.
TLDR
Interaction kinetic-based resistance profiles showed that phenethylthiazolylthiourea compounds were relatively insensitive to the studied substitutions, compared to what has been reported elsewhere.
...
1
2
3
4
5
...