The impact of the nelfinavir resistance-conferring mutation D30N on the susceptibility of HIV-1 subtype B to other protease inhibitors

Santos, André F.; Soares, Marcelo A.

doi:10.1590/s0074-02762011000200010

Cited by 6 publications

(6 citation statements)

References 23 publications

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“…Last, mutation of N88D alone is associated primarily with resistance to nelfinavir (NFV). However, N88D is common in association with D30N, which exerts a synergistic effect on resistance to NFV, and the double mutant shows 260-fold increased K i value for NFV compared to wild-type. − To analyze binding of compound 1 with various drug-resistant mutants, crystal structures were determined of its complexes with PR I47V , PR L76V , PR V82A , and PR N88D . Analysis of these structures and the relative inhibition values will assist in the design of improved drugs for resistant HIV.…”

Section: Introductionmentioning

confidence: 99%

Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring

Chang

Zhang

et al. 2012

J. Med. Chem.

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GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1′ (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25 to 1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PRI47V, PRL76V, PRV82A and PRN88D. Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PRI47V and PRL76V, and the altered charge of PRN88D are associated with significant local structural changes compared to the wild-type PRWT, while substitution of alanine in PRV82A increases the size of the S1′ subsite. The P1′ pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PRWT with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.

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Section: Introductionmentioning

confidence: 99%

Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring

Chang

Zhang

et al. 2012

J. Med. Chem.

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“…The well-known D30N exchange has been largely studied and described as the primary Nelfinavir resistance mutation [2], [6], [11]–[13]. In our 10 ns simulations, this mutation did not affect the flap dynamics of the PR-NF complex, which stayed in a closed conformation.…”

Section: Discussionmentioning

confidence: 66%

“…For instance, D30N mutation causes high-level resistance to Nelfinavir (NF) [1], [2] and V32I is associated to reduced susceptibility to all PIs, except Saquinavir [1], [3]. However, the effect of the presence of alternative amino acids in these same sites is still unclear.…”

Section: Introductionmentioning

confidence: 99%

New Insights into the In Silico Prediction of HIV Protease Resistance to Nelfinavir

et al. 2014

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The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.

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“…Several studies showed that, for the major PI DR mutations observed by UDPS, I54V/A/S/T/L/M mutations reduced the drug susceptibility to most PIs and most occurred in patients receiving multiple PIs [48–51]. It has been reported that D30N is exclusively selected by NFV and confers resistance to this drug [52]. For the accessory mutations observed using UDPS, M36I is a consensus mutation frequently occurring in non-B subtypes and particularly in PI-experienced patients [50, 53].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Drug Resistance Profiles of Patients Infected with CRF07_BC Using Phenotypic Assay and Ultra-Deep Pyrosequencing

Huang

Wang

et al. 2017

PLoS ONE

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The usefulness of ultra-deep pyrosequencing (UDPS) for the diagnosis of HIV-1 drug resistance (DR) remains to be determined. Previously, we reported an explosive outbreak of HIV-1 circulating recombinant form (CRF) 07_BC among injection drug users (IDUs) in Taiwan in 2004. The goal of this study was to characterize the DR of CRF07_BC strains using different assays including UDPS. Seven CRF07_BC isolates including 4 from early epidemic (collected in 2004–2005) and 3 from late epidemic (collected in 2008) were obtained from treatment-naïve patient’s peripheral blood mononuclear cells. Viral RNA was extracted directly from patient’s plasma or from cultural supernatant and the pol sequences were determined using RT-PCR sequencing or UDPS. For comparison, phenotypic drug susceptibility assay using MAGIC-5 cells (in-house phenotypic assay) and Antivirogram were performed. In-house phenotypic assay showed that all the early epidemic and none of the late epidemic CRF07_BC isolates were resistant to most protease inhibitors (PIs) (4.4–47.3 fold). Neither genotypic assay nor Antivirogram detected any DR mutations. UDPS showed that early epidemic isolates contained 0.01–0.08% of PI DR major mutations. Furthermore, the combinations of major and accessory PI DR mutations significantly correlated with the phenotypic DR. The in-house phenotypic assay is superior to other conventional phenotypic assays in the detection of DR variants with a frequency as low as 0.01%.

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The impact of the nelfinavir resistance-conferring mutation D30N on the susceptibility of HIV-1 subtype B to other protease inhibitors

Abstract: The human immunodeficiency virus type 1

Cited by 6 publications

References 23 publications

Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring

Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1′-Pyrrolidinone Ring

New Insights into the In Silico Prediction of HIV Protease Resistance to Nelfinavir

Characterization of the Drug Resistance Profiles of Patients Infected with CRF07_BC Using Phenotypic Assay and Ultra-Deep Pyrosequencing

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