Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation

// Hemayet Ullah 1 , Wangheng Hou 2 , Sivanesan Dakshanamurthy 3 and Qiyi Tang 2 1 Department of Biology, Howard University, Washington, DC 20059, USA 2 Department of Microbiology, Howard University College of Medicine, Washington, DC 20059, USA 3 Department of Oncology, Clinical and Experimental Therapeutics Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA Correspondence to: Sivanesan Dakshanamurthy, email: sd233@georgetown.edu Qiyi Tang, email: qiyi.tang@howard.edu Hemayet Ullah, email: hullah@howard.edu Keywords: host targeted antiviral (HTA); herpes simplex virus (HSV); receptor for activated C kinase 1 (RACK1); RACK1 inhibitor; internal ribosomal entry site (IRES) Received: November 15, 2018     Accepted: April 21, 2019     Published: May 14, 2019 ABSTRACT Due to the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs. Viruses require host factors to translate their transcripts, and targeting the host factor(s) offers a unique opportunity to develop broad antiviral drugs. It is well documented that some viruses utilize a host protein, Receptor for Activated C Kinase 1 (RACK1), to translate their mRNAs using a viral mRNA secondary structure known as the Internal Ribosomal Entry Site (IRES). RACK1 is essential for the translation of many viruses including hepatitis C (HCV), polio, Drosophila C (DCV), Dengue, Cricket Paralysis (CrpV), and vaccinia viruses. In addition, HIV-1 and Herpes Simplex virus (HSV-1) are known to use IRES as well. Therefore, host RACK1 protein is an attractive target for developing broad antiviral drugs. Depletion of the host’s RACK1 will potentially inhibit virus replication. This background study has led us to the development of novel antiviral therapeutics, such as RACK1 inhibitors. By utilizing the crystal structure of the RACK1A protein from the model plant Arabidopsis and using a structure based drug design method, dozens of small compounds were identified that could potentially bind to the experimentally determined functional site of the RACK1A protein. The SPR assays showed that the small compounds bound strongly to recombinant RACK1A protein. Here we provide evidence that the drugs show high efficacy in inhibition of HSV-1 proliferation in a HEp-2 cell line. The drug showed similar efficacy as the available anti-herpes drug acyclovir and showed supralinear effect when applied in a combinatorial manner. As an increasing number of viruses are reported to use host RACK1 proteins, and more than 100 diverse animals and plant disease-causing viruses are known to use IRES-based translation, these drugs can be established as host-targeted broad antiviral drugs.