Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library

Eur J Med Chem. 2018 Oct 5:158:478-492. doi: 10.1016/j.ejmech.2018.09.029.

Gaochan Wu ¹, Waleed A Zalloum ², Megan E Meuser ³, Lanlan Jing ¹, Dongwei Kang ¹, Chin-Ho Chen ⁴, Ye Tian ¹, Fangfang Zhang ⁵, Simon Cocklin ⁶, Kuo-Hsiung Lee ⁷, Xinyong Liu ⁸, Peng Zhan ⁹

Affiliations

1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
2 Department of Pharmacy, Faculty of Health Science, American University of Madaba, P.O Box 2882, Amman, 11821, Jordan.
3 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA.
4 Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.
5 Institute of Biochemical and Biotechnological Drug, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
6 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA, USA. Electronic address: sc349@drexel.edu.
7 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. Electronic address: khlee@unc.edu.
8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
9 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.

PMID: 30243152 DOI: 10.1016/j.ejmech.2018.09.029

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 NL_4-3 reference strain. In particular, compound 13m exhibited the greatest potency and lowest toxicity within this new series with an EC₅₀ value of 4.33 μM and CC₅₀ value of >57.74 μM (SI > 13.33). These values are very similar to the lead compound PF-74 (EC₅₀ = 5.95 μM, CC₅₀ > 70.50 μM, 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.

Keywords

CuAAC; HIV-1; HIV-1 capsid protein; Molecular dynamics simulation; Phenylalanine derivatives; Surface plasmon resonance.

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