Molecular Targets for AIDS Therapy

Mitsuya, Hiroaki; Yarchoan, Robert; Broder, Samuel

doi:10.1126/science.1699273

Cited by 719 publications

(332 citation statements)

References 212 publications

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“…29 Both viral and cellular TK can catalyze this step. 30 The subsequent rate-limiting step by thymidylate kinase results in the production of relatively low levels (compared with the predominant form of AZTMP) of AZTDP and AZTTP.…”

Section: Elevated Levels Of Aztmp In Pel Cellsmentioning

confidence: 99%

Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Ghosh

Wood

Boise

et al. 2003

Blood

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The survival of viral mediated lymphomas depends upon constitutive nuclear factor kappa B (NF-B) activity. AIDS-related human herpesvirus type 8-associated primary effusion lymphoma (PEL) responds poorly to chemotherapy and is almost invariably fatal. We have previously demonstrated that the antiviral combination of interferon alpha (IFN-␣) and azidothymidine (AZT) induces apoptosis in PEL cell lines. We therefore used these agents as therapy for an AIDS patient with PEL.

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Section: Elevated Levels Of Aztmp In Pel Cellsmentioning

confidence: 99%

Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Ghosh

Wood

Boise

et al. 2003

Blood

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“…Human immunodeficiency virus type 1 (HIV-1) drug resistance arises from mutations in the viral genome, specifically in the regions that encode the molecular targets of therapy (Mitsuya et al 1990) in such a way that the protease (PR) and reverse transcriptase (RT) enzymes function is no longer inhibited by the drug, leaving the virus to replicate freely. Therapy options for the management of HIV-1 disease include nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs).…”

mentioning

confidence: 99%

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

Simonetti

Schatzmayr

Simonetti

2003

Mem. Inst. Oswaldo Cruz

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“…Two types of drugs that inhibit HIV-I polymerase activity are nucleoside and nonnucleoside inhibitors. Although several members of the former class, such as 3"azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine, and 2',3'-dideoxyinosine, have shown promise in the clinic (Mitsuya et al, 1990;De Clercq, 1992), their usefulness is limited by toxicity and the emergence of drug-resistant mutants. In addition, these compounds appear to have undesirably broad specificity in that their 5"triphosphate forms interact with other RTs, as well as with cellular DNA polymerases (Larder & Kemp, 1990;St.…”

mentioning

confidence: 99%

“…RT, which is virally encoded, is essential to the replication of HIV-I; it converts the viral RNA genome into a double-stranded linear DNA intermediate that is subsequently integrated into the host cell DNA (Goff, 1990;Mitsuya et al, 1990). HIV-I RT consists of one 66-kDa polypeptide chain (p66), containing a polymerase domain and an RNase H domain, and one 51-kDa polypeptide chain (PSI) containing only the polymerase domain (DimarzoVeronese et al, 1986).…”

mentioning

confidence: 99%

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Smith¹,

Hughes²,

Boyer³

et al. 1995

Protein Science

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Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subset of the protein surrounding the binding pocket region,Results from the minimizations of solvated complexes of 2-cyclopropyl-4-methyl-5,l l-dihydro-5H-dipyrido[3,2-b :2',3'-e][ 1,4]diazepin-6-0ne (nevirapine), a-anilino-2, 6-dibromophenylacetamide (a-APA), and 8-chloro-tetrahydro-imidazo(4,5,l-jk)(l,4)-benzodiazepin-2(IH)-thione (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as 7r-electron donors to aromatic side-chain residues surrounding the pocket. However, side-chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC,, values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. interactions of the inhibitors with individual residues correlate with crystallographic and site-specific mutational data. a-Stacking interactions are important in binding and correlate with drug HOMO RHF/6-31G* energies. Modeling results are discussed with respect to the mechanism of complex formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV-1 RT that are resistant to the currently available drugs.

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Molecular Targets for AIDS Therapy

Abstract: for their helpful reviews of this manuscript and J. Folkman for providing me with the inspiration to do research in this field.

Cited by 719 publications

References 212 publications

Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NF-κB

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

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