Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Ghosh, Arun K.; Martyr, Cuthbert D.; Kassekert, Luke A.; Nyalapatla, Prasanth R.; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.; Amano, Masayuki; Mitsuya, Hiroaki

doi:10.1039/C5OB01930C

Title: Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Abstract

Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. Here, the majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.

Authors:

Ghosh, Arun K. ^[1]; Martyr, Cuthbert D. ^[1]; Kassekert, Luke A. ^[1]; Nyalapatla, Prasanth R. ^[1]; Steffey, Melinda ^[1]; Agniswamy, Johnson ^[2]; Wang, Yuan-Fang ^[2]; Weber, Irene T. ^[2]; Amano, Masayuki ^[3]; Mitsuya, Hiroaki ^[4]

Purdue Univ., West Lafayette, IN (United States)
Georgia State Univ., Atlanta, GA (United States)
Kumamoto Univ. School of Medicine (Japan)
Kumamoto Univ. School of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States)

Publication Date:: Wed Oct 14 00:00:00 EDT 2015

Research Org.:: Argonne National Laboratory (ANL), Argonne, IL (United States)

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

OSTI Identifier:: 1228099

Grant/Contract Number:: W-31–109-Eng-38; GM53386; GM62920

Resource Type:: Accepted Manuscript

Journal Name:: Organic and Biomolecular Chemistry

Additional Journal Information:: Journal Volume: 13; Journal Issue: 48; Journal ID: ISSN 1477-0520

Publisher:: Royal Society of Chemistry

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; HIV-1 protease inhibitors; antiviral; darunavir; multidrug-resistant; design; synthesis; X-ray crystal structure; backbone binding

Citation Formats


                    Ghosh, Arun K., Martyr, Cuthbert D., Kassekert, Luke A., Nyalapatla, Prasanth R., Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., Amano, Masayuki, and Mitsuya, Hiroaki. Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands.  United States: N. p., 2015. 
Web.  doi:10.1039/C5OB01930C.

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                    Ghosh, Arun K., Martyr, Cuthbert D., Kassekert, Luke A., Nyalapatla, Prasanth R., Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., Amano, Masayuki, & Mitsuya, Hiroaki. Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands.  United States.  https://doi.org/10.1039/C5OB01930C

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                    Ghosh, Arun K., Martyr, Cuthbert D., Kassekert, Luke A., Nyalapatla, Prasanth R., Steffey, Melinda, Agniswamy, Johnson, Wang, Yuan-Fang, Weber, Irene T., Amano, Masayuki, and Mitsuya, Hiroaki. Wed .  
"Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands".  United States.  https://doi.org/10.1039/C5OB01930C.  https://www.osti.gov/servlets/purl/1228099.

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@article{osti_1228099,

  title        = {Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands},

  author       = {Ghosh, Arun K. and Martyr, Cuthbert D. and Kassekert, Luke A. and Nyalapatla, Prasanth R. and Steffey, Melinda and Agniswamy, Johnson and Wang, Yuan-Fang and Weber, Irene T. and Amano, Masayuki and Mitsuya, Hiroaki},

  abstractNote = {Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. Here, the majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.},

  doi          = {10.1039/C5OB01930C},

  journal      = {Organic and Biomolecular Chemistry},

  number       = 48,

  volume       = 13,

  place        = {United States},

  year         = {Wed Oct 14 00:00:00 EDT 2015},

  month        = {Wed Oct 14 00:00:00 EDT 2015}

}

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Works referencing / citing this record:

Lactols in Asymmetric Sequential Organo- and Gold-Catalysis: Synthesis of Densely Functionalized Epimeric Bicyclic O,O-Acetals
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Title: Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Abstract

Citation Formats

Asymmetric Induction in the [2,3] Wittig Rearrangement by Chiral Substituents in the Allyl Moiety journal, February 1988

Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Crystal Structure journal, August 2011

PRODRG : a tool for high-throughput crystallography of protein–ligand complexes journal, July 2004

Asymmetric Induction and Simple Diastereoselectivity in the [2,3] Wittig Rearrangement of Ester Enolates journal, April 1989

High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains journal, April 2004

Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes journal, January 2001

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Overview of the CCP 4 suite and current developments journal, March 2011

A short history of SHELX journal, December 2007

Enantioselective Synthesis of (+)-(2 R ,3 S ,6 R )-Decarestrictine L journal, April 1998

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The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study journal, June 2011

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A facile and enantiospecific synthesis of 2(S)- and 2 (R)[1′(S)-azido-2-phenylethyl]oxirane journal, January 1992

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Asymmetric Induction in the [2,3] Wittig Rearrangement by Chiral Substituents in the Allyl Moiety
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PRODRG : a tool for high-throughput crystallography of protein–ligand complexes
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Asymmetric Induction and Simple Diastereoselectivity in the [2,3] Wittig Rearrangement of Ester Enolates
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High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains
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Darunavir (Prezista): A HIV-1 Protease Inhibitor for Treatment of Multidrug-Resistant HIV
book, January 2010

Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Studies
journal, August 2015

Overview of the CCP 4 suite and current developments
journal, March 2011

A short history of SHELX
journal, December 2007

Enantioselective Synthesis of (+)-(2 R ,3 S ,6 R )-Decarestrictine L
journal, April 1998

Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV
journal, January 2012

The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study
journal, June 2011

A simple, continuous fluorometric assay for HIV protease
journal, December 1990

Features and development of Coot
journal, March 2010

Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance
journal, September 2006

Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance
journal, January 2008

A graphical user interface to the CCP 4 program suite
journal, June 2003

Mitsunobu and Related Reactions: Advances and Applications
journal, June 2009

HAART in treatment-experienced patients in the 21st century: the audacity of hope
journal, January 2009

Design, Synthesis, and X-ray Structure of Substituted Bis-tetrahydrofuran (Bis-THF)-Derived Potent HIV-1 Protease Inhibitors
journal, January 2011

Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors (II)
journal, April 2015

A facile and enantiospecific synthesis of 2(S)- and 2 (R)[1′(S)-azido-2-phenylethyl]oxirane
journal, January 1992

Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors
journal, March 2012

Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X-ray Studies
journal, August 2013

Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters: HIV protease mutants altering hydrophobic clusters
journal, August 2010

Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV
journal, December 2007

Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro
journal, September 2003

Facile Synthesis of Highly Functionalized N- Methyl Amino Acid Esters without Side-Chain Protection
journal, September 2005

Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors
journal, March 2011

Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naive Individuals
journal, January 2009

Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors
journal, September 2010

Phaser crystallographic software
journal, July 2007

Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P ₂ Ligands: Structure−Activity Studies and Biological Evaluation
journal, January 2011

Lactols in Asymmetric Sequential Organo- and Gold-Catalysis: Synthesis of Densely Functionalized Epimeric Bicyclic O,O-Acetals
journal, October 2017

Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors
journal, June 2018

Novel Protease Inhibitors Containing C-5-Modified bis -Tetrahydrofuranylurethane and Aminobenzothiazole as P2 and P2′ Ligands That Exert Potent Antiviral Activity against Highly Multidrug-Resistant HIV-1 with a High Genetic Barrier against the Emergence of Drug Resistance
journal, May 2019