scholarly journals Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1718 ◽  
Author(s):  
Roberto Romeo ◽  
Daniela Iannazzo ◽  
Lucia Veltri ◽  
Bartolo Gabriele ◽  
Beatrice Macchi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nucleoside Analogs ◽  
Hiv Reverse Transcriptase ◽  
Inhibitor Activity ◽  
Virus Activity ◽  
Immunodeficiency Virus ◽  
Hiv Rt ◽  
Rt Inhibitors ◽  
Anti Hiv ◽  
Nanomolar Range

The pyrimidine nucleus is a versatile core in the development of antiretroviral agents. On this basis, a series of pyrimidine-2,4-diones linked to an isoxazolidine nucleus have been synthesized and tested as nucleoside analogs, endowed with potential anti-HIV (human immunodeficiency virus) activity. Compounds 6a–c, characterized by the presence of an ethereal group at C-3, show HIV reverse transcriptase (RT) inhibitor activity in the nanomolar range as well as HIV-infection inhibitor activity in the low micromolar with no toxicity. In the same context, compound 7b shows only a negligible inhibition of RT HIV.

scholarly journals Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

1993 ◽  
Vol 4 (5) ◽  
pp. 301-308 ◽  
Author(s):  
H. Zhang ◽  
L. Vrang ◽  
T. Unge ◽  
B. Öberg
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mixed Type ◽  
Competitive Inhibition ◽  
Wild Type ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptases ◽  
Immunodeficiency Virus ◽  
Hiv Rt ◽  
Rt Inhibitors

Two mutants of human immunodeficiency virus (HIV) reverse transcriptase (RT), Tyr181 to Cys and Leu100 to He, have been prepared and characterized by use of various inhibitors. As compared to wild type RT the mutant RT's had lower Kcat/Km values. The Km values were lower with heteropolymeric than with homopolymeric template-primers. Inhibition by phosphonoformate was of mixed type with both wild-type and mutant RT's and the mutants were less sensitive to phosphonoformate than the wild type RT. The non-nucleoside RT inhibitors 9-CI-TIBO and L-697,661 gave a non-competitive inhibition with respect to substrate of the wild type RT. The mutant RT's were inhibited at higher concentrations, showing a mixed type of inhibition with respect to substrate. ddGTP caused a competitive inhibition of wild type and mutant RT's with respect to substrate. RT preparations with different mutations are useful in rapidly characterizing the interaction between various inhibitors and HIV RT and thus facilitate the development of new inhibitors.

scholarly journals Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β-l(−)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus β-d(+) Nucleoside Analogs In Vitro

1998 ◽  
Vol 42 (7) ◽  
pp. 1799-1804 ◽  
Author(s):  
Ginger E. Dutschman ◽  
Edward G. Bridges ◽  
Shwu-Huey Liu ◽  
Elizabeth Gullen ◽  
Xin Guo ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Nucleoside Analogs ◽  
Drug Combinations ◽  
Mitochondrial Toxicity ◽  
Hiv Reverse Transcriptase ◽  
Immunodeficiency Virus ◽  
Deoxycytidine Deaminase ◽  
Anti Hiv

ABSTRACT 2′,3′-Dideoxy-2′,3′-didehydro-β-l(−)-5-fluorocytidine [l(−)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of l(−)Fd4C plus 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T, or stavudine) or 3′-azido-3′-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with l(−)Fd4C in combination with 2′,3′-dideoxycytidine (ddC, or zalcitabine) or 2′,3′-dideoxyinosine (ddI, or didanosine). This β-l(−) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 μM. As we previously reported for other β-l(−) nucleoside analogs, l(−)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the Km is 100 μM.l(−)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also,l(−)Fd4C was not a substrate for deoxycytidine deaminase.l(−)Fd4C 5′-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by l(−)Fd4C in two-drug combinations favors the further development of l(−)Fd4C as an anti-HIV agent.

scholarly journals The Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation I132M Confers Hypersensitivity to Nucleoside Analogs

2009 ◽  
Vol 83 (8) ◽  
pp. 3826-3833 ◽  
Author(s):  
Zandrea Ambrose ◽  
Brian D. Herman ◽  
Chih-Wei Sheen ◽  
Shannon Zelina ◽  
Katie L. Moore ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Nucleoside Analogs ◽  
Replication Capacity ◽  
Immunodeficiency Virus ◽  
Viral Replication Capacity ◽  
Rt Inhibitors ◽  
Hiv 1

ABSTRACT We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity.

scholarly journals Mechanism of Anti-Human Immunodeficiency Virus Activity of β-d-6-Cyclopropylamino-2′,3′-Didehydro-2′,3′-Dideoxyguanosine

2005 ◽  
Vol 49 (5) ◽  
pp. 1994-2001 ◽  
Author(s):  
Adrian S. Ray ◽  
Brenda I. Hernandez-Santiago ◽  
Judy S. Mathew ◽  
Eisuke Murakami ◽  
Carey Bozeman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Oral Delivery ◽  
Mononuclear Cells ◽  
Cellular Metabolism ◽  
Nucleoside Analogs ◽  
Immunodeficiency Virus ◽  
Moderate Resistance ◽  
Hiv Drugs ◽  
Anti Hiv

ABSTRACT To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2′,3′-didehydro-2′,3′-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 ± 0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2′-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2′-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2′,3′-dideoxycytidine and 2′,3′-didehydro-3′-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.

scholarly journals Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

2001 ◽  
Vol 45 (8) ◽  
pp. 2276-2279 ◽  
Author(s):  
Mark A. Winters ◽  
Thomas C. Merigan
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Gene Mutations ◽  
Nucleoside Analogs ◽  
Drug Susceptibility ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors

ABSTRACT The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.

Human Immunodeficiency Virus Reverse Transcriptase (HIV-RT)

2018 ◽  
pp. 100-127
Author(s):  
Anuradha Singh ◽  
Ramendra K. Singh
Keyword(s):  
Human Immunodeficiency Virus ◽  
Life Cycle ◽  
Drug Design ◽  
Reverse Transcriptase ◽  
Rational Drug Design ◽  
Mechanism Of Inhibition ◽  
Rational Drug ◽  
Immunodeficiency Virus ◽  
Hiv Rt ◽  
Rt Inhibitors

Reverse transcriptase (RT) is a multifunctional enzyme in the life cycle of human immunodeficiency virus and represents a primary target for drug discovery against HIV-1 infection. Two classes of RT inhibitors, the nucleoside and the non-nucleoside RT inhibitors, are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. This chapter deals with the salient features of HIV-RT that make it an attractive target for rational drug design and chemotherapeutic intervention in the management of acquired immunodeficiency syndrome. Further, the role of RT in the viral life cycle, the ways the drugs act to inhibit the normal functions of RT, and the mechanisms that the virus adapts to evade the available drugs have been discussed. Computational strategies used in rational drug design accompanied by a better understanding of RT, its mechanism of inhibition and drug resistance, discussed in this chapter, shall provide a better platform to develop effective RT inhibitors.

scholarly journals An Overview of the Cure of HIV/AIDS Harbal Therapy Containing Natural Antioxidant, Vitamins and Minerals

2021 ◽  
Vol 6 (3) ◽  
pp. p26
Author(s):  
Silas David Emmanuel ◽  
I. M. Bugaje ◽  
S. M. Mohammmad
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Aloe Vera ◽  
Hiv Reverse Transcriptase ◽  
Mortality And Morbidity ◽  
Neem Leaves ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv Aids

Purposes: The unprecedented and sequence through which an estimate of 25 million lives have gone to their early grave yard through Acquired Immune-deficiency Syndrome HIV/AIDS can never be quantified; since, when it was first describes in 1981. In 2017/2018 by (UNAIDS) it was estimated globally for about 36.9millions people were living with Human, Immunodeficiency Virus (HIV) so to say. Henceforth the progress made in the field of treatment in the form of Antiretroviral Therapy (ART) disease has not been fully ascertain for the cure of HIV/AIDS; except, perpetual clinical suppressions. Thus, the current challenges that man kinds faces with the used of perpetual intake of antiretroviral therapy (clinical suppression)/artificial vaccine is un-justifiable. However, search for HIV therapy have open a new chapter in the search for novel drugs from Kaduna Polytechnic procedure. This review focuses on vitamins, antioxidant, mineral and supplement as sources of in-hibitors or eradications for human immunodeficiency virus type-1 (HIV) reverse transcriptase. Objective: To assess whether vitamins, antioxidant, minerals supplement are effective and safe in eradicating mortality and morbidity among populace with HIV infection. Selection criteria: Randomized control trials were selected that compared the effect of vitamins (A, C, D, E, K,), antioxidant, minerals and supplement with regard to treatment measures in HIV infected persons. Methods: To prevent authors bias, based on a systematic search of literature; anti-HIV reverse transcriptase activity of some plant’s species like those of Eucalyptus leaves, Garlic fresh fruits, Baobab leaves, aloe vera, neem leaves, moringa leaves, bitter leaves etc. respectively. Thus, these medicinal plants contain an appreciable or above values antioxidant compound or photochemical like those of Phenolic, anthraquinone, tannin, falconoid, terpenoid, lignin, coumarins etc. respectively. Contrarywise, these phytochemical compounds have been exploited traditionally for the cure of many diseases as well as inhibition of viral replication/transcription. Further investigations have shared more light through which phytochemicals compounds inhibit virus replication either during the viral entry inside the host cell or during their replication. Originality: in view of the current investigation or to accelerate drug discovery and innovation, this review recommends the urgent need to tap into the enrich locally available endogenous knowledge of putative anti- HIV/AIDS, photochemical and their derivatives, (reverse pharmacology, determine pan assay, interferences compounds, microbial enzyme metabolites relationship and their mechanisms to treat virial diseases.

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