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

Publication ,  Journal Article
Wu, G; Zalloum, WA; Meuser, ME; Jing, L; Kang, D; Chen, C-H; Tian, Y; Zhang, F; Cocklin, S; Lee, K-H; Liu, X; Zhan, P
Published in: Eur J Med Chem
October 5, 2018

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 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.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

October 5, 2018

Volume

158

Start / End Page

478 / 492

Location

France

Related Subject Headings

  • Small Molecule Libraries
  • Phenylalanine
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • HIV Infections
  • Click Chemistry
  • Capsid
  • Anti-HIV Agents
 

Citation

APA
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ICMJE
MLA
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Wu, G., Zalloum, W. A., Meuser, M. E., Jing, L., Kang, D., Chen, C.-H., … Zhan, P. (2018). Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library. Eur J Med Chem, 158, 478–492. https://doi.org/10.1016/j.ejmech.2018.09.029
Wu, Gaochan, Waleed A. Zalloum, Megan E. Meuser, Lanlan Jing, Dongwei Kang, Chin-Ho Chen, Ye Tian, et al. “Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.Eur J Med Chem 158 (October 5, 2018): 478–92. https://doi.org/10.1016/j.ejmech.2018.09.029.
Wu G, Zalloum WA, Meuser ME, Jing L, Kang D, Chen C-H, et al. Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library. Eur J Med Chem. 2018 Oct 5;158:478–92.
Wu, Gaochan, et al. “Discovery of phenylalanine derivatives as potent HIV-1 capsid inhibitors from click chemistry-based compound library.Eur J Med Chem, vol. 158, Oct. 2018, pp. 478–92. Pubmed, doi:10.1016/j.ejmech.2018.09.029.
Wu G, Zalloum WA, Meuser ME, Jing L, Kang D, Chen C-H, Tian Y, Zhang F, Cocklin S, Lee K-H, Liu X, Zhan P. 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.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

October 5, 2018

Volume

158

Start / End Page

478 / 492

Location

France

Related Subject Headings

  • Small Molecule Libraries
  • Phenylalanine
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • HIV Infections
  • Click Chemistry
  • Capsid
  • Anti-HIV Agents