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

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

doi:10.1016/j.bbrc.2019.08.126

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

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Abstract

Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, here antiviral compound 2 derived from 1 with fused tricyclic group at P2, extended amino-benzothiazole P2’ ligand and two fluorine atoms on P1 shows 16-fold better inhibition of PR20 enzyme activity. Crystal structures of PR20 and wild-type PR complexes reveal how the extra groups of 2 counteract the expanded ligand-binding pocket, dynamic flaps, and faster dimer dissociation of PR20.

Authors:

Kneller, Daniel W. ^[1]; Agniswamy, Johnson ^[1]; Ghosh, Arun K. ^[2];

^[1]

Georgia State Univ., Atlanta, GA (United States)
Purdue Univ., West Lafayette, IN (United States)

Publication Date:: Thu Aug 29 00:00:00 EDT 2019

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)

OSTI Identifier:: 1572565

Alternate Identifier(s):: OSTI ID: 1703108

Grant/Contract Number:: W-31-109-Eng-38; AI150461; AI150466

Resource Type:: Accepted Manuscript

Journal Name:: Biochemical and Biophysical Research Communications

Additional Journal Information:: Journal Volume: 519; Journal Issue: 1; Journal ID: ISSN 0006-291X

Publisher:: Elsevier

Country of Publication:: United States

Language:: ENGLISH

Subject:: 60 APPLIED LIFE SCIENCES; drug resistance; HIV protease; antiretroviral inhibitor; structure-based design; x-ray crystallography

Citation Formats


                    Kneller, Daniel W., Agniswamy, Johnson, Ghosh, Arun K., and Weber, Irene T. Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20.  United States: N. p., 2019. 
Web.  doi:10.1016/j.bbrc.2019.08.126.

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                    Kneller, Daniel W., Agniswamy, Johnson, Ghosh, Arun K., & Weber, Irene T. Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20.  United States.  https://doi.org/10.1016/j.bbrc.2019.08.126

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                    Kneller, Daniel W., Agniswamy, Johnson, Ghosh, Arun K., and Weber, Irene T. Thu .  
"Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20".  United States.  https://doi.org/10.1016/j.bbrc.2019.08.126.  https://www.osti.gov/servlets/purl/1572565.

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@article{osti_1572565,

  title        = {Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20},

  author       = {Kneller, Daniel W. and Agniswamy, Johnson and Ghosh, Arun K. and Weber, Irene T.},

  abstractNote = {Drug-resistance threatens effective treatment of HIV/AIDS. Clinical inhibitors, including darunavir (1), are ineffective for highly resistant protease mutant PR20, however, here antiviral compound 2 derived from 1 with fused tricyclic group at P2, extended amino-benzothiazole P2’ ligand and two fluorine atoms on P1 shows 16-fold better inhibition of PR20 enzyme activity. Crystal structures of PR20 and wild-type PR complexes reveal how the extra groups of 2 counteract the expanded ligand-binding pocket, dynamic flaps, and faster dimer dissociation of PR20.},

  doi          = {10.1016/j.bbrc.2019.08.126},

  journal      = {Biochemical and Biophysical Research Communications},

  number       = 1,

  volume       = 519,

  place        = {United States},

  year         = {Thu Aug 29 00:00:00 EDT 2019},

  month        = {Thu Aug 29 00:00:00 EDT 2019}

}

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