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


The cover for issue 35 of Oncotarget features Figure 8A (TOP PANEL), "Hep-2 cells were incubated with the indicated compounds in the presence of HSV1-Luc virus at a concentration of 4 X 106 pfu/ml media," and Figure 2A (BOTTOM PANEL), "Docked Model of RACK1A with SD-29 at the Y248 phosphorylation site," by Ullah, et al.

Viruses require host factors to translate their transcripts, and targeting the host factor offers a unique opportunity to develop broad antiviral drugs.

Therefore, host RACK1 protein is an attractive target for developing broad antiviral drugs.

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.

Figure 1: (A) Shown are sample two receptor-based three-point pharmacophore models generated on the RACK1A phosphorylation site with exclusion spheres colored pink, geometric and distance constraints (flexible) shown as lines and filled white circles as centers. HP-hydrophobic; D-donor; A-acceptor. (B) Ligand-based pharmacophore model generated on SD-29 with pharmacophore constraints acceptor, donor, hydrophobic ring, and hydrophilic sites represented filled circles. Structures of compounds SD-29-12 and SD-29-14 are shown.

Dr. Sivanesan Dakshanamurthy from the Department of Oncology, Clinical and Experimental Therapeutics Program, Lombardi Comprehensive Cancer Center at the Georgetown University Medical Center in Washington, DC 20057, USA, Dr. Qiyi Tang from the Department of Microbiology at the Howard University College of Medicine in Washington, DC 20059, USA and Dr. Hemayet Ullah from the Department of Biology at the Howard University in Washington, DC 20059, USA said, "With the small number of molecular targets in viruses and the rapid evolution of viral genes, it is very challenging to develop specific antiviral drugs."

In addition to regulating the cap-independent IRES-mediated translation of some RNA viruses, RACK1 has recently been shown to regulate translation of capped mRNAs encoded by vaccinia virus, a DNA virus.

Pox virus infection leads to the modification of host RACK1 to mimic a plant-like state that remodels the host ribosome, such that Poly-A repeat-containing mRNAs erroneously generated by slippage of the viral RNA polymerase confer a translational advantage to the virus.

To date, although IRES elements have been widely reported in RNA viruses, only a very limited number of IRES elements have been reported in a few DNA viruses, including Kaposis sarcoma-associated herpesvirus, Epstein-Barr virus, herpes simplex virus, murine gammaherpesvirus 68, Mareks disease virus, and simian vacuolating virus 40.

The IRES website documents more than 68 viruses with references for IRES evidence, including Human immunodeficiency virus type 1, Human immunodeficiency virus type 2; Herpes Simplex Virus-1, Epstein-Barr virus, Encephalomyocarditis virus, Foot-and-mouth disease virus, IBV Infectious bronchitis virus, Bovine viral diarrhea virus, Classical swine fever virus, as well as some plant viruses.

This strategy of targeting a host factor, instead of the virus directly, potentially circumvents the damaging effect of resistance developed by viruses after the prolonged use of promising antiviral drugs.

The Dakshanamurthy/Tang/Ullah Research Team concluded, "Future endeavors to generate next generation drugs targeting the host RACK1 protein with enhanced efficacy will advance this approach to a significantly new level where direct targeting anti-viral drugs are slowly being rendered as non-effective in term of their effective durability".

Full text - https://doi.org/10.18632/oncotarget.26907

Correspondence to - Sivanesan Dakshanamurthy - [email protected], Qiyi Tang - [email protected], and Hemayet Ullah - [email protected]

Keywords - host targeted antiviral (HTA), herpes simplex virus (HSV), receptor for activated C kinase 1 (RACK1), RACK1 inhibitor, internal ribosomal entry site (IRES)

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