Comparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups

1995 ◽  
Vol 26 (2) ◽  
pp. 117-132 ◽  
Author(s):  
R BUCKHEIT ◽  
V FLIAKASBOLTZ ◽  
W DECKER ◽  
J ROBERSON ◽  
T STUP ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Virus Isolates ◽  
Hiv 1

scholarly journals A Diarylsulphone Non-Nucleoside Reverse Transcriptase Inhibitor with a Unique Sensitivity Profile to Drug-Resistant Virus Isolates

1996 ◽  
Vol 7 (5) ◽  
pp. 243-252 ◽  
Author(s):  
R.W. Buckheit ◽  
V. Fliakas-Boltz ◽  
J.D. Russell ◽  
M. Snow ◽  
L.A. Pallansch ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Rt Inhibitors ◽  
Reverse Transcriptase Inhibitor ◽  
Virus Isolates ◽  
Hiv 1 ◽  
Sensitivity Profile

Structure-activity relationship evaluations with a series of diarylsulphone non-nucleoside reverse transcriptase (RT) inhibitors indicated that the steric properties of the molecule and compound lipophilicity primarily contributed to the overall level of activity of the compounds against human immunodeficiency virus type 1 (HIV-1). The most active compounds in the diarylsulphone series had an orthonitro group and yielded anti-HIV activity at sub-micromolar concentrations. Compounds of the diarylsulphone class exhibited antiviral properties similar to other members of the pharmacologic class of HIV-1 specific non-nucleoside reverse transcriptase inhibitors, including activity in a wide variety of established and primary human cells, activity against a wide variety of laboratory and clinical virus isolates, and activity when challenged at high multiplicity of infection. Synergistic inhibition of HIV-1 was observed when the diarylsulphone NSC 667952 was used with the nucleoside analogues AZT, ddl, 3TC and d4T, the protease inhibitor KNI 272 and the sulphonated dye resobene; additive effects were observed when NSC 667952 was used with the nucleoside analogue ddC and other non-nucleoside RT inhibitors. The diarylsulphones exhibited a unique sensitivity profile when evaluated against both virus isolates and purified reverse transcriptase containing non-nucleoside reverse transcriptase inhibitor resistance-engendering mutations. Unlike other members of the class of non-nucleoside compounds, NSC 667952 remained active against virus isolates with the L100I amino acid change in the RT. The compound was, however, highly sensitive to Y181C., K103N and K101E amino acid changes in the RT. The diarylsulphone selected for resistant virus populations which possessed the Y181C amino acid change in the reverse transcriptase and which exhibited enhanced sensitivity to the non-nucleoside inhibitors calanolide A and costatolide.

scholarly journals Characterization of a Mutant HIV-1 Reverse Transcriptase Resistant to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150)

1994 ◽  
Vol 5 (4) ◽  
pp. 278-281
Author(s):  
H. Samanta ◽  
R. Rose ◽  
A. K. Patick ◽  
C. M. Bechtold ◽  
J. Trimble ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Serial Passage ◽  
Transcriptase Inhibitor ◽  
Viral Resistance ◽  
Resistant Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

A virus strain resistant to R82150, a non-nucleoside reverse transcriptase (NNRT) inhibitor (tetrahydro-imidazo [4,5, 1- jk] [1,4] benzodiazepine-2(1 H)-thione), was isolated following serial passage of HIV-1 RF in CEM-SS cells. The virus is cross-resistant to another non-nucleoside reverse transcriptase inhibitor, TGG-II-23A [1,4-dimethyl-1-[5,5-dimethyl-2-oxazoionyl]-naphthalen-2-one), but remains susceptible to AZT, DDI, D4T and phosphonoformate (PFA). DNA sequencing of reverse transcriptase genes from resistant virus indicated that R82150 selects for amino acid alterations Y181C and V108I. In vitro mutagenized reverse transcriptase and recombinant HIV-1 (pNL4-3) carrying either of the mutations have been generated. Genotypic and phenotypic analyses identified V108I as an unreported R82150-associated mutation. Both reverse transcriptase and viral resistance assays indicated that the resistance conferred by the V108I mutation is 7-fold less than that conferred by Y181C.

scholarly journals Synthesis of 1-benzyl-3-(3,5-dimethylbenzyl)Uracil Derivatives with Potential Anti-HIV Activity

2011 ◽  
Vol 22 (2) ◽  
pp. 57-65 ◽  
Author(s):  
Yohei Isono ◽  
Norikazu Sakakibara ◽  
Paula Ordonez ◽  
Takayuki Hamasaki ◽  
Masanori Baba ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Structural Modifications ◽  
Half Maximal Effective Concentration ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv Agents ◽  
Substituted 1 ◽  
Anti Hiv ◽  
Hiv 1

Background: Nine novel uracil analogues were synthesized and evaluated as inhibitors of HIV-1. Methods: Key structural modifications included replacement of the 6-chloro group of 1-benzyl-6-chloro-3-(3,5-dimethylbenzyl)uracil by other functional groups or N1-alkylation of 3-(3,5-dimethylbenzyl)-5-fluorouracil. Results: These compounds showed only micromolar potency against HIV-1 in MT-4, though two of them; 6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil were highly potent (half maximal effective concentration =0.067 and 0.069 μM) and selective (selectivity index =685 and 661), respectively. Structure–activity relationships among the newly synthesized uracil analogues suggest the importance of the H-bond formed between 6-amino group of 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil and amide group of HIV-1 reverse transcriptase. Conclusions: We discovered two 6-substituted 1-benzyl-3-(3,5-dimethylbenzyl) uracils, (6-azido-1-benzyl-3-(3,5-dimethylbenzyl) uracil and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl) uracil) as novel anti-HIV agents. These compounds should be further pursued for their toxicity and pharmacokinetics in vivo as well as antiviral activity against non-nucleoside reverse transcriptase inhibitor-resistant strains.

Synthesis and anti-HIV-1 Activity of [1-[2′,5′-Bis-O-(Tert-Butyldimethylsilyl)-β-L-Ribofuranosyl]Thymine]-3′-Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide) (L-TSAO-T), the L-enantiomer of the Highly Specific HIV-1 Reverse Transcriptase Inhibitor TSAO-T

1995 ◽  
Vol 6 (6) ◽  
pp. 365-370 ◽  
Author(s):  
S. T. Ingate ◽  
M.-J. Camarasa ◽  
E. De Clercq ◽  
J. Balzarini
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Antiretroviral Activity

The L-isomer of the potent HIV-1-RT inhibitor TSAO-T has been stereospecifically synthesized and tested for its ‘ in vitro’ antiretroviral activity against HIV-1. Unlike the D-isomer, the L-isomer did not show appreciable inhibition of HIV-1 replication. The cytotoxicity was comparable with the cytotoxicity of the D-enantiomer.

scholarly journals In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

2006 ◽  
Vol 80 (9) ◽  
pp. 4440-4446 ◽  
Author(s):  
Mohammad M. Hossain ◽  
Michael A. Parniak
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Microbicidal Activity ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTI-resistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10- to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt ≥ NVPR > UCR ≥ EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 μM UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTI-based microbicide formulations.

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP

2014 ◽  
Vol 16 (45) ◽  
pp. 24763-24783 ◽  
Author(s):  
M. Alcolea Palafox
Keyword(s):  
Proton Transfer ◽  
Conformational Analysis ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Transfer Mechanism ◽  
Hiv Reverse Transcriptase ◽  
Dft Methods ◽  
Reverse Transcriptase Inhibitor ◽  
Anti Hiv ◽  
Hiv 1

A proton-transfer mechanism is proposed for the first phosphorylation step of the nucleoside HIV-1 reverse transcriptase inhibitor AZT (3′-azido-3′ deoxythymidine) by interacting with ATP.

scholarly journals TMC125, a Novel Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor Active against Nonnucleoside Reverse Transcriptase Inhibitor-Resistant Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 48 (12) ◽  
pp. 4680-4686 ◽  
Author(s):  
Koen Andries ◽  
Hilde Azijn ◽  
Theo Thielemans ◽  
Donald Ludovici ◽  
Michael Kukla ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Wild Type ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 μM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of α1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.

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