Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor

Ferris, Robert G.; Hazen, Richard; Roberts, G.T.; Clair, M H St; Chan, Jason S.; Romines, Karen R.; Freeman, G. G.; Tidwell, Jeffrey H.; Schaller, Lee T.; Cowan, Jill R.; Short, Steven A.; Weaver, K.; Selleseth, Dean W.; Moniri, Kelly R.; Boone, Lawrence R.

doi:10.1128/aac.49.10.4046-4051.2005

Cited by 55 publications

(42 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…40 Benzopheneone NNRTIs 1, 2, 3, and the latter's prodrug 4 were synthesized and characterized as reported in earlier papers. [23][24][25][26] Anti-HIV-1 Activity and Resistance Profile of 1 in Cell Culture Systems. The anti-HIV-1 activity of the prototype benzophenone 1 was tested against a wider panel of mutant viruses than previously reported 23 using the methods described in earlier studies.…”

Section: Methodsmentioning

confidence: 99%

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

et al. 2008

Self Cite

View full text Add to dashboard Cite

Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.

show abstract

Section: Methodsmentioning

confidence: 99%

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Compound anti-HIV-1 activity was determined in HeLa-CD4-LTR-␤-gal (14) by the method of Ferris et al (7).…”

Section: Compoundsmentioning

confidence: 99%

In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

Hazen¹,

Harvey²,

Ferris³

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC 50 s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC 50 s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC 50 s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

show abstract

“…E138K has previously been selected in vitro by other broadspectrum NNRTIs (4,8,13,17,20). However, it has low prevalence (0.5%) in clinical samples (43) and only little impact on susceptibility to narrow-spectrum NNRTIs.…”

mentioning

confidence: 99%

Characterization of the E138K Resistance Mutation in HIV-1 Reverse Transcriptase Conferring Susceptibility to Etravirine in B and Non-B HIV-1 Subtypes

Asahchop

Oliveira

Wainberg

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

We have selected for resistance to etravirine (ETR) and efavirenz (EFV) in tissue culture using three subtype B, three subtype C, and two CRF02_AG clinical isolates, grown in cord blood mononuclear cells. Genotypic analysis was performed at baseline and at various weeks of selection. Phenotypic resistance in regard to ETR, EFV, and nevirapine (NVP) was evaluated at weeks 25 to 30 for all ETR-selected viruses and in viral clones that contained specific resistance mutations that were inserted by site-directed mutagenesis into pNL-4.3 and AG plasmids. The results show that ETR selected mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y, and M230L and that E138K was the first of these to emerge in most instances. The time to the emergence of resistance was longer in the case of ETR (18 weeks) compared to EFV (11 weeks), and no differences in the patterns of emergent mutations could be documented between the B and non-B subtypes. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. ETR-selected virus showed a high degree of cross-resistance to NVP but not to EFV. We identified K101Q, E138K, V179E, V189I, G190E, and H221Y as mutations not included among the 17 currently recognized resistance-associated mutations for ETR.

show abstract

Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor

Cited by 55 publications

References 15 publications

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

Characterization of the E138K Resistance Mutation in HIV-1 Reverse Transcriptase Conferring Susceptibility to Etravirine in B and Non-B HIV-1 Subtypes

Contact Info

Product

Resources

About