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      Combining New Non-Nucleoside Reverse Transcriptase Inhibitors (RTIs) with AZT Results in Strong Synergism against Multi-RTI-Resistant HIV-1 Strains

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          Abstract

          Reverse transcriptase inhibitors (RTIs), including nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs), are critical antiretroviral drugs for the treatment of human immunodeficiency virus (HIV) infection. Emergence of multi-RTI resistance calls for the development of more potent therapeutics or regimens against RTI-resistant strains. Here, we demonstrated that combining azidothymidine (AZT) with a new NNRTIs under development, diarylpyridine (DAPA)-2e, diarylanilin (DAAN)-14h, or DAAN-15h, resulted in strong synergism against infection by divergent HIV-1 strains, including those resistant to NRTIs and NNRTIs, suggesting the potential for developing these novel NNRTIs as salvage therapy for HIV/acquired immune deficiency syndrome (AIDS) patients.

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          TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1.

          Koen Andries, Hilde Azijn, Theo Thielemans … (2004)
          Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 microM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.
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            Retroviral reverse transcriptases.

            Alon Herschhorn, Amnon Hizi (2010)
            Reverse transcription is a critical step in the life cycle of all retroviruses and related retrotransposons. This complex process is performed exclusively by the retroviral reverse transcriptase (RT) enzyme that converts the viral single-stranded RNA into integration-competent double-stranded DNA. Although all RTs have similar catalytic activities, they significantly differ in several aspects of their catalytic properties, their structures and subunit composition. The RT of human immunodeficiency virus type-1 (HIV-1), the virus causing acquired immunodeficiency syndrome (AIDS), is a prime target for the development of antiretroviral drug therapy of HIV-1/AIDS carriers. Therefore, despite the fundamental contributions of other RTs to the understanding of RTs and retrovirology, most recent RT studies are related to HIV-1 RT. In this review we summarize the basic properties of different RTs. These include, among other topics, their structures, enzymatic activities, interactions with both viral and host proteins, RT inhibition and resistance to antiretroviral drugs.
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              BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine.

              Nadia Rosenthal, Suzanne M. Skoog, Thomas Merluzzi … (1991)
              A series of dipyridodiazepinones have been shown to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. The lead compound, BI-RG-587, had a 50% inhibitory concentration of 84 nM against HIV-1 reverse transcriptase activity. This compound reduced plaque formation of HIV-1 in HeLa cells expressing the CD4 receptor by 50% at 15 nM. BI-RG-587 at comparable concentrations inhibited the production of p24 antigen following the acute infection of CEM T-lymphoblastoid cells or primary human monocyte-derived macrophages with HIV-1. No inhibitory effects against HIV-2 or against three picornaviruses were detected. Zidovudine (3'-azido-3'-deoxythymidine [AZT])-susceptible and AZT-resistant isolates of HIV-1 were equally susceptible to BI-RG-587. AZT and BI-RG-587 exhibited synergistic inhibition of HIV-1BRU at all concentrations examined.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 02 July 2018
                Publication date Collection: July 2018
                Volume: 23
                Issue: 7
                Electronic Location Identifier: 1599
                Affiliations
                [1 ]College of Life Sciences, Hebei Agricultural University, Baoding 071001, China; feiyu1110@ 123456hotmail.com (F.Y.); qwertydaiyu@ 123456163.com (Y.D.); luxin0409@ 123456163.com (X.L.)
                [2 ]Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Fudan University, 130 Dong An Rd., Xuhui District, Shanghai 200032, China; wenli3708@ 123456gmail.com (W.L.); wang_qian@ 123456fudan.edu.cn (Q.W.)
                [3 ]Research Center of Chinese Jujube, Hebei Agricultural University, Baoding 071001, China; lily850908@ 123456163.com
                [4 ]Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China; lanxie4@ 123456icloud.com
                [5 ]Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
                Author notes
                [* ]Correspondence: shibojiang@ 123456fudan.edu.cn ; Tel.: +86-21-54237673
                [†]

                These authors contributed equally to this work.

                Article
                Publisher ID: molecules-23-01599
                DOI: 10.3390/molecules23071599
                PMC ID: 6099689
                PubMed ID: 30004408
                SO-VID: 913bed6a-a51f-4dd8-8f03-95c05ea44e3f
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 24 May 2018
                Date accepted : 28 June 2018
                Categories
                Subject: Brief Report

                Keywords: hiv-1,haart,nnrtis,antiviral activity,combination,synergism
                Data availability:
                Keywords: hiv-1, haart, nnrtis, antiviral activity, combination, synergism

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