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Journal article
Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library
European journal of medicinal chemistry, v 158, pp 478-492
05 Oct 2018
PMID: 30243152
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of HIV-1 replication and is considered an important, clinically unexploited therapeutic target. As such, small drug-like molecules that inhibit this critical HIV-1 protein have become a priority for several groups. Therefore, in this study we explore small molecule targeting of the CA protein, and in particular a very attractive inter-protomer pocket. We report the design, parallel synthesis, and anti-HIV-1 activity evaluation of a series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors synthesized via Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. We demonstrate robust inhibitory activity over a range of potencies against the HIV-1 NL4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC50 value of 4.33 mu M and CC50 value of >57.74 mu M (SI > 13.33). These values are very similar to the lead compound PF-74 (EC50= 5.95 mu M, CC50 > 70.50 mu M, SI > 11.85) in our assay, despite significant structural difference. Furthermore, we demonstrate via surface plasmon resonance (SPR) binding assays that 13m interacts robustly with recombinant HIV-1 CA and exhibits antiviral activity in both the early and late stages of HIV-1 replication. Overall, the novel parallel synthesis and structure-activity relationships (SARs) identified within this study set the foundation for further rational optimization and discovery of CA-targeting compounds with improved potency. (C) 2018 Elsevier Masson SAS. All rights reserved.
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Details
- Title
- Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library
- Creators
- Gaochan Wu - Shandong UniversityWaleed A. Zalloum - American University of MadabaMegan E. Meuser - Drexel UniversityLanlan Jing - Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Minist Educ,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R ChinaDongwei Kang - Shandong UniversityChin-Ho Chen - Duke UniversityYe Tian - Shandong UniversityFangfang Zhang - Shandong UniversitySimon Cocklin - Drexel UniversityKuo-Hsiung Lee - Shandong UniversityXinyong Liu - Shandong UniversityPeng Zhan - Shandong University
- Publication Details
- European journal of medicinal chemistry, v 158, pp 478-492
- Publisher
- Elsevier
- Number of pages
- 15
- Grant note
- R01GM125396 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) 2017JC006 / Fundamental Research Funds of Shandong University R56AI118415 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) 2016WLJH32 / Young Scholars Program of Shandong University (YSPSDU) 81420108027 / Key Project of NSFC for International Cooperation 2017CXGC1401 / Key research and development project of Shandong Province 81273354; 81573347 / National Natural Science Foundation of China (NSFC) 2015ZDJS04001 / Major Project of Science and Technology of Shandong Province T32MH079785 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) R56AI118415; R01GM125396 / NIH/NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000448094000035
- Scopus ID
- 2-s2.0-85053547658
- Other Identifier
- 991019167537304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal