HIV/AIDS remains a global epidemic and public health threat. Despite the development of effective antiretroviral drugs, therapy is not curative and is therefore life-long. Long-term therapy is often compromised by viral drug resistance mutations and incomplete adherence. The HIV-1 capsid represents an attractive target for therapy, though currently available inhibitors lack sufficient potency for clinical development. This project will develop a competition-based assay for small molecules targeting a specific pocket in the HIV-1 capsid and will adapt the assay for high-throughput screening of large compound libraries. The assay will be validated by screening a library of 10,000 small molecules and analyzing the hits for antiviral activity and cytotoxicity. This work will facilitate the identification of lead compounds for development of antivirals targeting the HIV-1 capsid, and will identify novel probes for HIV-1 capsid function.
Specific Aims :
Aim 1. Establish a competition-based high-throughput screening assay for small molecules that bind the H3-H4 pocket in HIV-1 CA.
Aim 2. Perform pilot screens to validate the assay.
Aim 3. Test the confirmed hits for antiviral activity against wild type HIV- and mutant viruses that are resistant to known capsid inhibitors.
HIV/AIDS remains a global epidemic and public health threat. Effective therapy requires long- term treatment with antiviral drugs, which is often compromised by viral resistance. This project will develop a competition-based assay for small molecules targeting a specific pocket in the HIV-1 capsid and will adapt the assay for high-throughput screening of large compound libraries, thus facilitating the identification of lead compounds for development of antivirals targeting the HIV-1 capsid.
| Rankovic, Sanela; Ramalho, Ruben; Aiken, Christopher et al. (2018) PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating. J Virol 92: |
| Carnes, Stephanie K; Sheehan, Jonathan H; Aiken, Christopher (2018) Inhibitors of the HIV-1 capsid, a target of opportunity. Curr Opin HIV AIDS 13:359-365 |
| Saito, Akatsuki; Ferhadian, Damien; Sowd, Gregory A et al. (2016) Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74. J Virol 90:5808-5823 |
| Halambage, Upul D; Wong, Jason P; Melancon, Bruce J et al. (2015) Microplate-based assay for identifying small molecules that bind a specific intersubunit interface within the assembled HIV-1 capsid. Antimicrob Agents Chemother 59:5190-5 |
