scholarly journals Defective Hydrophobic Sliding Mechanism and Active Site Expansion in HIV-1 Protease Drug Resistant Variant Gly48Thr/Leu89Met: Mechanisms for the Loss of Saquinavir Binding Potency

Biochemistry ◽  
2015 ◽  
Vol 54 (2) ◽  
pp. 422-433 ◽  
Author(s):  
Nathan E. Goldfarb ◽  
Meray Ohanessian ◽  
Shyamasri Biswas ◽  
T. Dwight McGee ◽  
Brian P. Mahon ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Sliding Mechanism ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals The Drug-Resistant Variant P167S Expands the Substrate Profile of CTX-M β-Lactamases for Oxyimino-Cephalosporin Antibiotics by Enlarging the Active Site upon Acylation

Biochemistry ◽  
2017 ◽  
Vol 56 (27) ◽  
pp. 3443-3453 ◽  
Author(s):  
Meha P. Patel ◽  
Liya Hu ◽  
Vlatko Stojanoski ◽  
Banumathi Sankaran ◽  
B. V. Venkataram Prasad ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Cephalosporin Antibiotics ◽  
Drug Resistant Variant

scholarly journals Backbone 1H, 13C, and 15N chemical shift assignment for HIV-1 protease subtypes and multi-drug resistant variant MDR 769

2012 ◽  
Vol 7 (2) ◽  
pp. 199-202 ◽  
Author(s):  
Xi Huang ◽  
Ian Mitchelle S. de Vera ◽  
Angelo M. Veloro ◽  
James R. Rocca ◽  
Carlos Simmerling ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Chemical Shift Assignment ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Shift Assignment ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Extreme Entropy–Enthalpy Compensation in a Drug-Resistant Variant of HIV-1 Protease

2012 ◽  
Vol 7 (9) ◽  
pp. 1536-1546 ◽  
Author(s):  
Nancy M. King ◽  
Moses Prabu-Jeyabalan ◽  
Rajintha M. Bandaranayake ◽  
Madhavi N. L. Nalam ◽  
Ellen A. Nalivaika ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Resistant Variant ◽  
Hiv 1 ◽  
Drug Resistant Variant

scholarly journals Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Paul L. Boyer ◽  
Kevin Melody ◽  
Steven J. Smith ◽  
Linda L. Dunn ◽  
Chris Kline ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Reverse Transcriptase ◽  
Active Site ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Hydrophobic Region ◽  
Nnrti Resistance ◽  
Hiv 1

ABSTRACTTwo mutations, G112D and M230I, were selected in the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) by a novel nonnucleoside reverse transcriptase inhibitor (NNRTI). G112D is located near the HIV-1 polymerase active site; M230I is located near the hydrophobic region where NNRTIs bind. Thus, M230I could directly interfere with NNRTI binding but G112D could not. Biochemical and virological assays were performed to analyze the effects of these mutations individually and in combination. M230I alone caused a reduction in susceptibility to NNRTIs, while G112D alone did not. The G112D/M230I double mutant was less susceptible to NNRTIs than was M230I alone. In contrast, both mutations affected the ability of RT to incorporate nucleoside analogs. We suggest that the mutations interact with each other via the bound nucleic acid substrate; the nucleic acid forms part of the polymerase active site, which is near G112D. The positioning of the nucleic acid is influenced by its interactions with the “primer grip” region and could be influenced by the M230I mutation.IMPORTANCEAlthough antiretroviral therapy (ART) is highly successful, drug-resistant variants can arise that blunt the efficacy of ART. New inhibitors that are broadly effective against known drug-resistant variants are needed, although such compounds might select for novel resistance mutations that affect the sensitivity of the virus to other compounds. Compound 13 selects for resistance mutations that differ from traditional NNRTI resistance mutations. These mutations cause increased sensitivity to NRTIs, such as AZT.

scholarly journals Evaluating the Substrate-Envelope Hypothesis: Structural Analysis of Novel HIV-1 Protease Inhibitors Designed To Be Robust against Drug Resistance

2010 ◽  
Vol 84 (10) ◽  
pp. 5368-5378 ◽  
Author(s):  
Madhavi N. L. Nalam ◽  
Akbar Ali ◽  
Michael D. Altman ◽  
G. S. Kiran Kumar Reddy ◽  
Sripriya Chellappan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Active Site ◽  
Crystallographic Analysis ◽  
Van Der Waals Interactions ◽  
Drug Resistant ◽  
Design Strategies ◽  
Resistance Mutations ◽  
Hiv 1 ◽  
Substrate Envelope

ABSTRACT Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to “lock” into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.

scholarly journals Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

2018 ◽  
Vol 61 (14) ◽  
pp. 6379-6397 ◽  
Author(s):  
Jian Zhang ◽  
Vasanthanathan Poongavanam ◽  
Dongwei Kang ◽  
Chiara Bertagnin ◽  
Huamei Lu ◽  
...  
Keyword(s):  
Influenza A ◽  
Drug Resistant ◽  
Resistant Variant ◽  
Drug Resistant Variant ◽  
Group 1

scholarly journals The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase

2018 ◽  
Vol 25 (10) ◽  
pp. 1268-1278.e3 ◽  
Author(s):  
Yuki Takamatsu ◽  
Debananda Das ◽  
Satoru Kohgo ◽  
Hironori Hayashi ◽  
Nicole S. Delino ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Active Site ◽  
Strong Interactions ◽  
Drug Resistant ◽  
Genetic Barrier ◽  
Hiv 1
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