Considerations for structure-based drug design targeting hiv-1 reverse transcriptase

TY - CHAP

T1 - Considerations for structure-based drug design targeting hiv-1 reverse transcriptase

AU - Arnold, Eddy

AU - Martinez, Sergio E.

AU - Bauman, Joseph D.

AU - Das, Kalyan

N1 - Publisher Copyright: © Springer Science+Business Media Dordrecht 2015.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - HIV-1 reverse transcriptase (RT) copies the viral single-stranded RNA genome into a double-stranded DNA version, and is a central target for anti-AIDS therapeutics. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have revealed different conformational and functional states of the enzyme. Rilpivirine and etravirine, two NNRTI drugs with high potency against common resistant variants, were discovered and developed through a multidisciplinary structure-based drug design effort. The resilience of rilpivirine and etravirine to resistance mutations results from the structural flexibility and compactness of these drugs. Recent insights into mechanisms of inhibition by the allosteric NNRTIs include (i) dynamic sliding of RT/NNRTI complexes along template-primers and (ii) displacement of the RT primer grip that repositions the 30-primer terminus away from the polymerase active site.

AB - HIV-1 reverse transcriptase (RT) copies the viral single-stranded RNA genome into a double-stranded DNA version, and is a central target for anti-AIDS therapeutics. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have revealed different conformational and functional states of the enzyme. Rilpivirine and etravirine, two NNRTI drugs with high potency against common resistant variants, were discovered and developed through a multidisciplinary structure-based drug design effort. The resilience of rilpivirine and etravirine to resistance mutations results from the structural flexibility and compactness of these drugs. Recent insights into mechanisms of inhibition by the allosteric NNRTIs include (i) dynamic sliding of RT/NNRTI complexes along template-primers and (ii) displacement of the RT primer grip that repositions the 30-primer terminus away from the polymerase active site.

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U2 - https://doi.org/10.1007/978-94-017-9719_6

DO - https://doi.org/10.1007/978-94-017-9719_6

M3 - Chapter

SN - 9789401797184

SP - 69

EP - 81

BT - Multifaceted Roles of Crystallography in Modern Drug Discovery

PB - Springer Netherlands

ER -