Enhanced In Vitro Inhibition of HIV-1 Replication by 3′-Fluoro-3′-deoxythymidine Compared to Several Other Nucleoside Analogs

ABSTRACT Using an indicator cell assay that directly quantifies viral replication, we show that human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2, respectively) exhibit similar sensitivities to 3′-azido-3′-deoxythymidine (zidovudine) as well as other nucleoside analog inhibitors of reverse transcriptase. These data support the use of nucleoside analogs for antiviral therapy of HIV-2 infection.

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Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.4.831 ◽

1997 ◽

Vol 41 (4) ◽

pp. 831-837 ◽

Cited By ~ 30

Author(s):

R W Buckheit ◽

M J Snow ◽

V Fliakas-Boltz ◽

T L Kinjerski ◽

J D Russell ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

In Vitro Selection ◽

Nucleoside Analogs ◽

Side Chain ◽

Resistant Virus ◽

Immunodeficiency Virus ◽

Virus Isolates ◽

Hiv 1

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.

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4′-C-Methyl-2′-Deoxyadenosine and 4′-C-Ethyl-2′-Deoxyadenosine Inhibit HIV-1 Replication

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01290-10 ◽

2011 ◽

Vol 55 (5) ◽

pp. 2379-2389 ◽

Cited By ~ 6

Author(s):

B. Christie Vu ◽

Paul L. Boyer ◽

Maqbool A. Siddiqui ◽

Victor E. Marquez ◽

Stephen H. Hughes

Keyword(s):

Reverse Transcriptase ◽

Dna Synthesis ◽

Cultured Cells ◽

Nucleoside Analogs ◽

Transcriptase Inhibitor ◽

Resistance Mutations ◽

Viral Dna ◽

Infected Cells ◽

Hiv 1

ABSTRACTIt is important to develop new anti-HIV drugs that are effective against the existing drug-resistant mutants. Because the excision mechanism is an important pathway for resistance to nucleoside analogs, we are preparing analogs that retain a 3′-OH and can be extended after they are incorporated by the viral reverse transcriptase. We show that 4′-C-alkyl-deoxyadenosine (4′-C-alkyl-dA) compounds can be phosphorylated in cultured cells and can inhibit the replication of HIV-1 vectors: 4′-C-methyl- and 4′-C-ethyl-dA show both efficacy and selectivity against HIV-1. The compounds are also effective against viruses that replicate using reverse transcriptases (RTs) that carry nucleoside reverse transcriptase inhibitor resistance mutations, with the exception of the M184V mutant. Analysis of viral DNA synthesis in infected cells showed that viral DNA synthesis is blocked by the incorporation of either 4′-C-methyl- or 4′-C-ethyl-2′-deoxyadenosine.In vitroexperiments with purified HIV-1 RT showed that 4′-C-methyl-2′-dATP can compete with dATP and that incorporation of the analog causes pausing in DNA synthesis. The 4′-C-ethyl compound also competes with dATP and shows a differential ability to block DNA synthesis on RNA and DNA templates. Experiments that measure the ability of the compounds to block DNA synthesis in infected cells suggest that this differential block to DNA synthesis also occurs in infected cells.

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In vitro inhibition of HIV-1 replication in autologous CD4+ T cells indicates viral containment by multifactorial mechanisms

Virologica Sinica ◽

10.1007/s12250-017-3992-9 ◽

2017 ◽

Vol 32 (6) ◽

pp. 485-494

Author(s):

Ting Tu ◽

Jianbo Zhan ◽

Danlei Mou ◽

Wei Li ◽

Bin Su ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

In Vitro Inhibition ◽

Hiv 1

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In Vitro Inhibition of Human Immunodeficiency Virus Type-1 (HIV-1) Reverse Transcriptase by Gold(III) Porphyrins

ChemBioChem ◽

10.1002/cbic.200300773 ◽

2004 ◽

Vol 5 (9) ◽

pp. 1293-1298 ◽

Cited By ~ 33

Author(s):

Raymond Wai-Yin Sun ◽

Wing-Yiu Yu ◽

Hongzhe Sun ◽

Chi-Ming Che

Keyword(s):

Human Immunodeficiency Virus ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immunodeficiency Virus ◽

In Vitro Inhibition ◽

Hiv 1

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In vitro inhibition of vesicular stomatitis virus replication by purified porcine Mx1 protein fused to HIV-1 Tat protein transduction domain (PTD)

Antiviral Research ◽

10.1016/j.antiviral.2013.05.009 ◽

2013 ◽

Vol 99 (2) ◽

pp. 149-157 ◽

Cited By ~ 15

Author(s):

Xiao-min Zhang ◽

Dan-Ni He ◽

Bin Zhou ◽

Ran Pang ◽

Ke Liu ◽

...

Keyword(s):

Vesicular Stomatitis Virus ◽

Virus Replication ◽

Protein Transduction ◽

Protein Transduction Domain ◽

Tat Protein ◽

Vesicular Stomatitis ◽

In Vitro Inhibition ◽

Hiv 1 ◽

Tat Protein Transduction Domain

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.5.1539-1546.2001 ◽

2001 ◽

Vol 45 (5) ◽

pp. 1539-1546 ◽

Cited By ~ 99

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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