Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties

Subbaiah, Murugaiah A. M.; Meanwell, Nicholas A.; Kadow, John F.

doi:10.1016/j.ejmech.2017.07.044

Cited by 27 publications

(41 citation statements)

References 44 publications

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Section: Figurementioning

confidence: 99%

Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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Transition state theory teaches that chemically stable mimics of enzymatic transition states will bind tightly to their cognate enzymes. Kinetic isotope effects combined with computational quantum chemistry provides enzymatic transition state information with sufficient fidelity to design transition state analogues. Examples are selected from various stages of drug development to demonstrate the application of transition state theory, inhibitor design, physicochemical characterization of transition state analogues, and their progress in drug development.

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Section: Figurementioning

confidence: 99%

Enzymatic Transition States and Drug Design

Schramm

2018

Chem. Rev.

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“…HIV PIs prevent cleavage of gag and gag-pol polyprotein in acutely and chronically infected cells, arresting maturation and thereby blocking the infectivity of nascent virions [51]. PIs act during maturation of viral particles in the late stage of HIV-1 life cycle, thus, these drugs can inhibit the release of infectious viral particles from an already infected cell thus preventing subsequent waves of infection.…”

Section: Hiv-protease Inhibitorsmentioning

confidence: 99%

Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages

et al. 2020

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Ongoing with current combinations of antiretroviral drugs for the treatment of Human Immunodeficiency Virus (HIV) infection can successfully maintain long-term suppression of HIV-1 replication in plasma. Still, none of these therapies is capable of extinguishing the virus from the long-lived cellular reservoir, including monocyte-derived macrophages (MDM), that means the principal obstacle to HIV cure. MDM are widely distributed in all tissues and organs, including central system nervous (CNS) where they represent the most frequent HIV-infected cells that means the principal obstacle to HIV cure. Current FDA-approved antiretroviral drugs target viral reverse transcriptase, protease, integrase, and entry processes (coreceptor or fusion blockade). It is desirable to continue to develop new antiretrovirals directed against alternative targets in the virus lifecycle in order to further optimize therapeutic options, overcome resistance to existing medications, and potentially contribute to the elimination of viral reservoirs.This review provides a comprehensive overview of the activity of antiretroviral drugs (classical and upcoming) in monocytes-derived macrophages (MDM). Defining the antiviral activity of these drugs in this important cellular HIV-1 reservoir provides crucial hints about their efficacy in HIV-1 infected patients.

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“…For example, Fosamprenavir is the phosphate ester prodrug of amprenavir that contains a hydrolyzable ester bond. The phosphate prodrug displays improved cellular absorption and diminished side effects [13]. Additionally, protease inhibitors are used in combination antiretroviral therapy (cART) regimes.…”

Section: Human Immunodeficiency Virus (Hiv) Protease Inhibitorsmentioning

confidence: 99%

Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

Chang

Kim

Lovell

et al. 2019

Viruses

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Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors.

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Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties

Cited by 27 publications

References 44 publications

Enzymatic Transition States and Drug Design

Enzymatic Transition States and Drug Design

Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages

Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

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