Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 158, Issue -, Pages 478-492Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.029
Keywords
HIV-1; Phenylalanine derivatives; HIV-1 capsid protein; CuAAC; Surface plasmon resonance; Molecular dynamics simulation
Categories
Funding
- National Natural Science Foundation of China (NSFC) [81273354, 81573347]
- Key Project of NSFC for International Cooperation [81420108027]
- Young Scholars Program of Shandong University (YSPSDU) [2016WLJH32]
- Fundamental Research Funds of Shandong University [2017JC006]
- Key research and development project of Shandong Province [2017CXGC1401]
- Major Project of Science and Technology of Shandong Province [2015ZDJS04001]
- NIH/NIAID [R56AI118415, R01GM125396]
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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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