Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Host-Targeted Antivirals Inhibit RACK1-mediated IRES Activities in HIV-1 Infection

Version 1 : Received: 25 April 2021 / Approved: 26 April 2021 / Online: 26 April 2021 (20:35:00 CEST)

How to cite: Malli, I.; Kumari, N.; Dubrovsky, L.; Ivanov, A.; Bukrinsky, M.; Nekhai, S.; Dakshanamurthy, S.; Ullah, H. Host-Targeted Antivirals Inhibit RACK1-mediated IRES Activities in HIV-1 Infection. Preprints 2021, 2021040692 (doi: 10.20944/preprints202104.0692.v1). Malli, I.; Kumari, N.; Dubrovsky, L.; Ivanov, A.; Bukrinsky, M.; Nekhai, S.; Dakshanamurthy, S.; Ullah, H. Host-Targeted Antivirals Inhibit RACK1-mediated IRES Activities in HIV-1 Infection. Preprints 2021, 2021040692 (doi: 10.20944/preprints202104.0692.v1).

Abstract

Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.

Subject Areas

RACK1; HIV-1; IRES; Hepatitis C; HCV; AZT; HTA; Host-targeted antiviral; HEK293T; SD29-14

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