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 Activity of SPD754, a New Deoxycytidine Nucleoside Reverse Transcriptase Inhibitor (NRTI), against 215 HIV-1 Isolates Resistant to Other NRTIs

2005 ◽  
Vol 16 (5) ◽  
pp. 295-302 ◽  
Author(s):  
Richard C. Bethell ◽  
Yolanda S. Lie ◽  
Neil T. Parkin
Keyword(s):  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Recombinant Viruses ◽  
Viral Susceptibility ◽  
Fold Reduction ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1 ◽  
Antiretroviral Activity

SPD754 (also known as AVX-754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor (NRTI) with antiretroviral activity against HIV-1 and HIV-2 in vitro and against recombinant viruses containing thymidine analogue mutations (TAMs). In order to better establish the activity of SPD754 against HIV-1 containing TAMs, twelve panels of up to twenty clinical isolates with defined TAM combinations were selected from the ViroLogic database. Phenotypic viral susceptibility to SPD754 and five other NRTIs was tested using the PhenoSense HIV assay and expressed as median fold-change compared with a reference strain. In total, 215 isolates were selected, representing four TAM patterns in both pathways by which TAMs accumulate clinically. The presence of five TAMs in the 41, 215 pathway, at codons 41, 67, 210, 215, and 219 of reverse transcriptase (RT), produced a median 1.8-fold reduction in SPD754 susceptibility, compared with fold reductions to zidovudine, lamivudine, abacavir, didanosine and tenofovir of 438, 4.8, 4.5, 1.4 and 3.6, respectively. Five TAMs in the 67, 70, 219 pathway (at codons 41, 67, 70, 215 and 219) reduced SPD754 susceptibility by a median 1.3-fold, compared with fold reductions for the aforementioned NRTIs of 108, 3.2, 3.0, 1.3 and 2.5, respectively. M184V addition reduced SPD754 susceptibility by 1.8-fold in the presence or absence of TAMs. SPD754 retains a substantial proportion of its antiviral activity against HIV-1 containing multiple TAMs, with or without the M184V mutation. These data suggest that SPD754 is a promising new NRTI for the treatment of NRTI-experienced HIV-infected patients.

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 The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes

2015 ◽  
Vol 59 (8) ◽  
pp. 4882-4888 ◽  
Author(s):  
Weisi Xu ◽  
Jianxiong Zhao ◽  
Jianping Sun ◽  
Qianqian Yin ◽  
Yan Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Therapeutic Index ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Highly Active ◽  
Hiv Drugs ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,in vitroresistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, thesein vitrodata indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

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.

scholarly journals In Vitro Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Nicholas S. Giacobbi ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Reverse Transcriptase ◽  
Genital Tract ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Rilpivirine (RPV), dapivirine (DPV), and MIV-150 are in development as microbicides. It is not known whether they will block infection of circulating nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant human immunodeficiency virus type 1 (HIV-1) variants. Here, we demonstrate that the activity of DPV and MIV-150 is compromised by many resistant viruses containing single or double substitutions. High DPV genital tract concentrations from DPV ring use may block replication of resistant viruses. However, MIV-150 genital tract concentrations may be insufficient to inhibit many resistant viruses, including those harboring K103N or Y181C.

scholarly journals 4′-Ethynyl Nucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human Immunodeficiency Virus Variants In Vitro

2001 ◽  
Vol 45 (5) ◽  
pp. 1539-1546 ◽  
Author(s):  
Ei-Ichi Kodama ◽  
Satoru Kohgo ◽  
Kenji Kitano ◽  
Haruhiko Machida ◽  
Hiroyuki Gatanaga ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Reverse Transcriptase ◽  
Wide Spectrum ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Multidrug Resistant ◽  
Human Immunodeficiency Viruses ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT A series of 4′-ethynyl (4′-E) nucleoside analogs were designed, synthesized, and identified as being active against a wide spectrum of human immunodeficiency viruses (HIV), including a variety of laboratory strains of HIV-1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined, 4′-E-2′-deoxycytidine (4′-E-dC), 4′-E-2′-deoxyadenosine (4′-E-dA), 4′-E-2′-deoxyribofuranosyl-2,6-diaminopurine, and 4′-E-2′-deoxyguanosine were the most potent and blocked HIV-1 replication with 50% effective concentrations ranging from 0.0003 to 0.01 μM in vitro with favorable cellular toxicity profiles (selectivity indices ranging 458 to 2,600). These 4′-E analogs also suppressed replication of various drug-resistant HIV-1 clones, including HIV-1M41L/T215Y, HIV-1K65R, HIV-1L74V, HIV-1M41L/T69S-S-G/T215Y, and HIV-1A62V/V75I/F77L/F116Y/Q151M. Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains carrying a variety of drug resistance-related amino acid substitutions isolated from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 agents had failed. The 4′-E analogs also blocked the replication of a non-nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1Y181C, and showed an HIV-1 inhibition profile similar to that of zidovudine in time-of-drug-addition assays. The antiviral activity of 4′-E-thymidine and 4′-E-dC was blocked by the addition of thymidine and 2′-deoxycytidine, respectively, while that of 4′-E-dA was not affected by 2′-deoxyadenosine, similar to the antiviral activity reversion feature of 2′,3′-dideoxynucleosides, strongly suggesting that 4′-Eanalogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4′-E analogs as potential therapeutics for infection with multidrug-resistant HIV-1 is warranted.

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