Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Kneller, D.W.; Agniswamy, Johnson; Ghosh, Arun K.; Weber, Irene T.

doi:10.1016/j.bbrc.2019.08.126

Cited by 13 publications

(7 citation statements)

References 37 publications

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“…In the S2′ subsite the inhibitor's benzothiazole ring formed three hydrogen bonds with Asp-29′ and Asp-30′ of PR ( Fig. 5a), thereby replacing less favorable indirect water-mediated interaction in was observed with aniline group of darunavir 20,21 . In addition, the sulfur atom of the benzothiazole ring forms a close contact with carboxyl oxygen of Gly-48 with a distance of 3.7 Å, producing significant interactions that should result in a coplanar arrangement of the amide and the thiazole ring (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Bulut

Hattori

Aoki-Ogata

et al. 2020

Sci Rep

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HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs. Here, seven novel PIs were synthesized, by introducing single atom changes such as an exchange of a sulfur to an oxygen, scission of a single bond in P2′-cyclopropylaminobenzothiazole (or-oxazole), and/or P1-benzene ring with fluorine scan of mono-or bis-fluorine atoms around DRV's scaffold. X-ray structural analyses of the PIs complexed with wild-type Protease (PR Wt) and highly-multi-PI-resistance-associated PR DRV R P51 revealed that the PIs better adapt to structural plasticity in PR with resistance-associated amino acid substitutions by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the S2′-subsite. Furthermore, these PIs displayed increased cell permeability and extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for developing novel PIs with high potency against PI-resistant HIV-1 variants with a high genetic barrier. Over the last 3 decades, HIV-1 infection has remained a devastating disease with ~80 million people infected worldwide and nearly half of them have lost lives from the infection (https://www.avert.org/global-hiv-and-aids-statistics). However, the present combined antiretroviral therapy (cART) has been proven to potently suppress HIV-1 replication and to significantly prolong the survival of people with HIV-1 infection and AIDS. The inhibitors of HIV-1 protease (PR), an essential enzyme that cleaves gag and gag-pol polyproteins into mature functional proteins, are the key element of effective cART 1,2. Blocking the activity of PR leaves virions in an immature state, which are unable to infect cells, thus leading to restoration of the immune system 3. Currently, there are nine licensed HIV-1 protease inhibitors (PIs) with nanomolar ranges of inhibitory potency against wild type virus; however, none of them are able to eradicate the virus in the body 4,5. Moreover, drug-resistant HIV-1 variants often emerge during long-term therapy 6,7 , due to the error-prone virally-encoded reverse transcriptase (RT) 8. Darunavir (DRV) is a second-generation nonpeptidic PI, which is highly potent against wild-type HIV-1 (HIV WT) and has a high genetic barrier to the emergence of DRV-resistant variants, retaining its potent anti-HIV activity over long-term periods in clinical settings 9,10. Nevertheless, DRV-resistant variants have been reported

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Section: Resultsmentioning

confidence: 99%

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Bulut

Hattori

Aoki-Ogata

et al. 2020

Sci Rep

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“…Over the last two years, important results have been obtained with a new class of antivirals protease inhibitors (PIs) 11 [19,20]. 12 These inhibitors are characterized by significant antiviral activity, having a particular interest in the current therapeutic approach to the treatment of HIV [21] as well as in the treatment of hepatitis C [22,23].…”

Section: Discussionmentioning

confidence: 99%

Towards potential inhibitors of COVID-19 main protease M^pro by virtual screening and molecular docking study

Moujane

Zaki

Benaissa

et al. 2020

Journal of Taibah University for Science

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“…Some inhibitors also incorporate fluorine, which improves penetration of the central nervous system. We are currently evaluating the effectiveness of the new antiviral inhibitors for PR20 and other highly resistant mutants [ 86 , 87 ]. One example, GRL142, is shown in Figure 3 .…”

Section: Hiv Drug Resistancementioning

confidence: 99%

“…One example, GRL142, is shown in Figure 3 . This inhibitor exhibits 20-fold better affinity than darunavir for extremely resistant mutant PR20 [ 87 ] and is promising for further clinical development.…”

Section: Hiv Drug Resistancementioning

confidence: 99%

HIV Protease: Historical Perspective and Current Research

Weber

Wang

Harrison

2021

Viruses

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The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.

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Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Cited by 13 publications

References 37 publications

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Towards potential inhibitors of COVID-19 main protease M^pro by virtual screening and molecular docking study

HIV Protease: Historical Perspective and Current Research

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Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Cited by 13 publications

References 37 publications

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, high genetic barrier, and adaptation to the HIV protease plasticity

Towards potential inhibitors of COVID-19 main protease Mpro by virtual screening and molecular docking study

HIV Protease: Historical Perspective and Current Research

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Towards potential inhibitors of COVID-19 main protease M^pro by virtual screening and molecular docking study