Inhibiting early-stage events in HIV-1 replication by small-molecule targeting of the HIV-1 capsid.

Abstract

The HIV-1 capsid (CA) protein plays essential roles in both early and late stages of virl replication and has emerged as a novel drug target. We report hybrid structure-based virtual screening to identify small molecules with the potential to interact with the N-terminal domain (NTD) of HIV-1 CA and disrupt early, preintegration steps of the HIV-1 replication cycle. The small molecule 4,4'-[dibenzo[b,d]furan-2,8-diylbis(5-phenyl-1H-imidazole-4,2-diyl)]dibenzoic acid (CK026), which had anti-HIV-1 activity in single- and multiple-round infections but failed to inhibit viral replication in peripheral blood mononuclear cells (PBMCs), was identified. Three analogues of CK026 with reduced size and better drug-like properties were synthesized and assessed. Compound I-XW-053 (4-(4,5-diphenyl-1H-imidazol-2-yl)benzoic acid) retained all of the antiviral activity of the parental compound and inhibited the replication of a diverse panel of primary HIV-1 isolates in PBMCs, while displaying no appreciable cytotoxicity. This antiviral activity was specific to HIV-1, as I-XW-053 displayed no effect on the replication of SIV or against a panel of nonretroviruses. Direct interaction of I-XW-053 was quantified with wild-type and mutant CA protein using surface plasmon resonance and isothermal titration calorimetry. Mutation of Ile37 and Arg173, which are required for interaction with compound I-XW-053, crippled the virus at an early, preintegration step. Using quantitative PCR, we demonstrated that treatment with I-XW-053 inhibited HIV-1 reverse transcription in multiple cell types, indirectly pointing to dysfunction in the uncoating process. In summary, we have identified a CA-specific compound that targets and inhibits a novel region in the NTD-NTD interface, affects uncoating, and possesses broad-spectrum anti-HIV-1 activity.

• Authors: Sandhya Kortagere, Navid Madani, Marie K Mankowski, Arne Schön, Isaac Zentner, Gokul Swaminathan, Amy Princiotto, Kevin Anthony, Apara Oza, Luz-Jeannette Sierra, Shendra R Passic, Xiaozhao Wang, David M Jones, Eric Stavale, Fred C Krebs, Julio Martín-García, Ernesto Freire, Roger G Ptak, Joseph Sodroski, Simon Cocklin, Amos B Smith 3rd
• Journal: Journal of virology (J Virol) Vol. 86 Issue 16 Pg. 8472-81 (Aug 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22647699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Capsid Proteins

Topics

• Anti-HIV Agents (chemical synthesis, pharmacology, toxicity)
• Calorimetry
• Capsid Proteins (antagonists & inhibitors)
• Cell Line
• HIV-1 (drug effects, physiology)
• Humans
• Microbial Sensitivity Tests
• Protein Binding
• Real-Time Polymerase Chain Reaction
• Reverse Transcription (drug effects)
• Simian Immunodeficiency Virus (drug effects)
• Surface Plasmon Resonance
• Virus Internalization (drug effects)
• Virus Replication (drug effects)
• Virus Uncoating (drug effects)