SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Buckheit, Robert W.; Watson, Karen; Fliakas-Boltz, Valerie; Russell, J D; Loftus, Tracy L; Osterling, Mark C.; Turpin, Jocelyn; Pallansch, Luke A.; White, E. Lucile; Lee, J.-W.; Lee, S.-H.; Oh, Jisun; Kwon, Ho Seok; Chung, Sun G.; Cho, E.-H.

doi:10.1128/aac.45.2.393-400.2001

Cited by 72 publications

(44 citation statements)

References 40 publications

(29 reference statements)

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“…Taken together, the data point to a different mechanism of action of some of the 3"-substituted TSAO derivatives. The NNRTI (SJ-3366) has been reported to inhibit both HIV-1 and HIV-2 replication, and to inhibit HIV-1 RT but not HIV-2 RT [89]. This compound was found to interfere with entry of HIV as a second mechanism of action.…”

Section: "-Substituted Tsao Derivativesmentioning

confidence: 99%

TSAO Compounds: The Comprehensive Story of a Unique Family of HIV- 1 Specific Inhibitors of Reverse Transcriptase

Camarasa¹,

San‐Félix²,

Velázquez³

et al. 2004

CTMC

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Emergence of drug-resistant viral strains is one of the major milestones and the main cause for the failure of antiretroviral therapy. Combination of different anti-HIV agents has become the standard clinical practice to keep the viral load at low or even undetectable levels and to prevent emergence of virus-drug resistance. Among the human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors, the so called nonnucleoside RT inhibitors (NNRTIs) have gained a definitive place in the treatment of HIV infections in combination with nucleoside analogue RT inhibitors (NRTIs) and HIV protease inhibitors (PIs). The virus can be markedly suppressed for a relatively long period of time when exposed to multiple drug combination therapy (highly active antiretroviral therapy, HAART). TSAO derivatives are a peculiar group of highly functionalized nucleosides that belong to the so-called nonnucleoside RT inhibitors (NNRTIs). They exert their unique selectivity for HIV-1 through a specific interaction with the p51 subunit of HIV-1 RT. They are the first small molecules that seem to interfere with the dimerization process of the enzyme. This review covers the work carried out with this unique class of specific inhibitors of HIV-1 reverse transcriptase, including structure activity relationship studies (SAR), its mechanism of action, resistance studies, model of interaction with the enzyme, etc.

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Section: "-Substituted Tsao Derivativesmentioning

confidence: 99%

TSAO Compounds: The Comprehensive Story of a Unique Family of HIV- 1 Specific Inhibitors of Reverse Transcriptase

Camarasa¹,

San‐Félix²,

Velázquez³

et al. 2004

CTMC

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“…Pyrimidinedione [PYD; 1-(3-cyclopenten-1-ylmethyl)-5-ethyl-6-(3,5-dimethylbenzoyl)-2,4(1H,3H)] derivatives constitute a unique class of non-nucleoside reverse transcriptase inhibitors that also inhibit HIV entry through an unknown mechanism thought to target a conformational epitope formed prior to the fusion of the viral envelope with the host cellular membrane (5). The dual mechanisms of action, high potency, minimal toxicity to vaginal cells and natural flora and broad range of activity against wild-type and drug-resistant clinical viruses make these molecules attractive candidates for microbicide development.…”

mentioning

confidence: 99%

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Mahalingam

Simmons

Ugaonkar

et al. 2011

Antimicrob Agents Chemother

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Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels-3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation-for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months. In vitro release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The in vitro and ex vivo safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In an in vitro HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 g/ml for gel in culture media, which corresponds to ϳ0.001 M IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in in vivo models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

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“…7) Recently, Buckheit et al reported a unique and highly potent uracil derivative, 1-(3-cyclopenten-1-yl)methyl-6-(3,5-dimethylbenzoyl)-5-ethyl-2,4-pyrimidinedione (SJ-3366), which showed antiviral activity against HIV-2 as well as HIV-1. 8) Thereafter, many pyrimidine derivatives emerged as anti-HIV agents. 9,10) Against the background of these reports, we undertook a search for an anti-HIV agent by the structure-activity relationship (SAR) of the 1,3-disubstituted uracil 11) .…”

mentioning

confidence: 99%

Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

Maruyama

Kozai

Demizu

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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3-(3,5-Dimethylbenzyl)uracil (3) was treated with alkyl halides in the presence of alkali to give 1-substituted congeners. Condensation of 3 with alcohols using the Mitsunobu reaction was also employed as an alternative method. The anti-HIV-1 activity of 1-substituted analogues of 3-(3,5-dimethylbenzyl)uracil was evaluated according to previously established procedures. It appeared that the nitrogen of the 1-cyanomethyl group is important for anti-HIV-1 activity, suggesting interaction with the amino acid residue of HIV-1 reverse transcriptase. 1-Arylmethyl derivatives also showed good anti-HIV-1 activity; and that of 2-and 4-picolyl derivatives was particularly excellent. These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group.

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SJ-3366, a Unique and Highly Potent Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1 (HIV-1) That Also Inhibits HIV-2

Cited by 72 publications

References 40 publications

TSAO Compounds: The Comprehensive Story of a Unique Family of HIV- 1 Specific Inhibitors of Reverse Transcriptase

TSAO Compounds: The Comprehensive Story of a Unique Family of HIV- 1 Specific Inhibitors of Reverse Transcriptase

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Synthesis and Anti-HIV-1 and Anti-HCMV Activity of 1-Substituted 3-(3,5-Dimethylbenzyl)uracil Derivatives

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