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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • October 5, 2018

Published In

Volume / Issue

  • 158 /

Start / End Page

  • 478 - 492

PubMed ID

  • 30243152

Pubmed Central ID

  • PMC6550353

Electronic International Standard Serial Number (EISSN)

  • 1768-3254

Digital Object Identifier (DOI)

  • 10.1016/j.ejmech.2018.09.029


  • eng

Conference Location

  • France