scholarly journals Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors

2012 ◽  
Vol 56 (10) ◽  
pp. 5000-5008 ◽  
Author(s):  
Eugene L. Asahchop ◽  
Mark A. Wainberg ◽  
Richard D. Sloan ◽  
Cécile L. Tremblay
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Antiviral Drug ◽  
Transcriptase Inhibitor ◽  
Antiviral Resistance ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Genetic Barrier ◽  
Highly Active ◽  
Underlying Mechanisms

ABSTRACTHighly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

scholarly journals The Need for Development of New HIV-1 Reverse Transcriptase and Integrase Inhibitors in the Aftermath of Antiviral Drug Resistance

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Mark A. Wainberg
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Antiviral Drug ◽  
Antiviral Resistance ◽  
Strand Transfer ◽  
Reverse Transcriptase Inhibitors ◽  
Major Step ◽  
Genetic Barrier ◽  
Highly Active

The use of highly active antiretroviral therapy (HAART) involves combinations of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. There are two broad classes of reverse transcriptase inhibitors, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first classes of such compounds were developed, viral resistance against them has necessitated the continuous development of novel compounds within each class. This paper considers the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second line therapy and describes the patterns of resistance associated with their use, as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with low genetic barrier are more commonly used in resource-limited settings. Their use results to the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings. More recently, the advent of integrase strand transfer inhibitors represents another major step forward toward control of HIV infection, but these compounds are also susceptible to problems of HIV drug resistance.

Tenofovir Disoproxil Fumarate

2003 ◽  
Vol 37 (6) ◽  
pp. 849-859 ◽  
Author(s):  
Shellee A Grim ◽  
Frank Romanelli
Keyword(s):  
Reverse Transcriptase ◽  
Tenofovir Disoproxil Fumarate ◽  
Highly Active Antiretroviral Therapy ◽  
Data Extraction ◽  
Single Agent ◽  
Transcriptase Inhibitor ◽  
Medline Search ◽  
Highly Active ◽  
Cell Counts ◽  
Hiv 1

OBJECTIVE: To review the pharmacology, virology, pharmacokinetics, efficacy, safety, resistance profile, and clinical use of tenofovir disoproxil fumarate. DATA SOURCES: A MEDLINE search was performed (1966–August 2002) using the following terms: tenofovir, tenofovir disoproxil fumarate, PMPA (9-( R)-[2-(phosphonomethoxy)propyl]adenine), and Viread. Abstracts from HIV-related meetings were reviewed. DATA EXTRACTION AND STUDY SELECTION: Publications and meeting abstracts regarding tenofovir were reviewed. The most recent and pertinent items were included. DATA SYNTHESIS: Tenofovir disoproxil fumarate is a nucleotide prodrug that is diphosphorylated to its active moiety, tenofovir diphosphate. In this form, tenofovir acts as a reverse transcriptase inhibitor to inhibit HIV-1 replication. In clinical trials, tenofovir was effective at suppressing HIV-1 RNA and boosting CD4+ cell counts. Tenofovir has a long intracellular half-life, which permits once-daily dosing. Since tenofovir does not interact with the cytochrome P450 pathway, it exhibits minimal drug interactions, with the exception of didanosine. Compared with other reverse transcriptase inhibitors, tenofovir may have advantages in terms of toxicity and medication adherence profiles. Ongoing studies are also analyzing tenofovir's activity against hepatitis B virus. CONCLUSIONS: Tenofovir has been shown to be active against HIV-1 in combination with other antiretrovirals. The drug's benefit as a single-agent intensifier of highly active antiretroviral therapy in treatment-experienced patients has been established, and preliminary data for treatment-naïve patients are encouraging.

scholarly journals The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes

2015 ◽  
Vol 59 (8) ◽  
pp. 4882-4888 ◽  
Author(s):  
Weisi Xu ◽  
Jianxiong Zhao ◽  
Jianping Sun ◽  
Qianqian Yin ◽  
Yan Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Therapeutic Index ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Highly Active ◽  
Hiv Drugs ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACTNonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 × 104. A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,in vitroresistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, thesein vitrodata indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.

scholarly journals DPC 817: a Cytidine Nucleoside Analog with Activity against Zidovudine- and Lamivudine-Resistant Viral Variants

2002 ◽  
Vol 46 (5) ◽  
pp. 1394-1401 ◽  
Author(s):  
Raymond F. Schinazi ◽  
John Mellors ◽  
Holly Bazmi ◽  
Sharon Diamond ◽  
Sena Garber ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Half Life ◽  
Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Plasma Half Life

ABSTRACT Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2′,3′-didehydro-2′,3′-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.

Current structure-based methods for designing non-nucleoside reverse transcriptase inhibitors

2019 ◽  
Vol 14 (8) ◽  
pp. 537-544
Author(s):  
Kathleen M Frey ◽  
Tasnim Tabassum
Keyword(s):  
Crystal Structure ◽  
Reverse Transcriptase ◽  
Nucleoside Reverse Transcriptase Inhibitor ◽  
Transcriptase Inhibitor ◽  
Hiv Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Antiretroviral Therapies ◽  
New Ideas ◽  
Inhibitor Drug ◽  
Reverse Transcriptase Inhibitor

In 2019, structure-based methods continue to guide the design of novel antiretroviral therapies targeting HIV reverse transcriptase. This Review summarizes key findings from reverse transcriptase–non-nucleoside reverse transcriptase inhibitor analog crystal structure complexes reported from 2015 to 2019. Results from the literature and structure analysis have informed new ideas for structure-guided non-nucleoside reverse transcriptase inhibitor drug design.

Sign in / Sign up

Export Citation Format

Share Document