Trivedi, J. and Alam, A. and Joshi, S. and Kumar, T.P. and Chippala, V. and Mainkar, P.S. and Chandrasekhar, S. and Chattopadhyay, S. and Mitra, D. (2019) A novel isothiocyanate derivative inhibits HIV-1 geneexpression and replication by modulating the nuclear matrix associated proteinSMAR1. Antiviral Research., 173.

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Abstract

The essential role of SMAR1 in HIV-1 transcription and LTR driven gene expression suggests SMAR1 as an HIV dependency factor (HDF) and a potential anti-HIV therapeutic target. Here, we report for the first time, anti-HIV activity of 8 novel isothiocyanate (ITC) derivatives that differentially stabilise SMAR1. Out of 8 novel ITC derivatives, SCS-OCL-381 was observed to inhibit HIV-1 replication most significantly at the noncytotoxic concentration in reporter T-cell line, CEM-GFP. Further, the highly conserved anti-HIV activity of SCS-OCL-381 is a cell type, virus isolate and viral load independent phenomena and is approximately 3 fold more effective than the representative ITC, Sulforaphane (SFN). Further, SCS-OCL-381 does not hamper the activity of viral enzymes reverse transcriptase, integrase and protease. Mechanistically, SCS-OCL-381 stabilises SMAR1 which, otherwise undergoes proteasomal degradation upon HIV-1 infection in T-cells. This stabilisation results in the recruitment of repressor complex on HIV-1 LTR resulting in repression of LTR mediated transcription and gene expression. These inhibitory consequences were further confirmed by reporter based LTR activity assays in different cell lines. Taken together, these findings highlight the anti-HIV potential of novel ITC derivatives by the stabilisation of SMAR1 and strongly support further in vivo characterisation and potential translational applications of SCS-OCL-381.

Item Type:	Article
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	25 Feb 2020 04:42
Last Modified:	25 Feb 2020 04:42
URI:	http://nccs.sciencecentral.in/id/eprint/774

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