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Oncotarget: Functional inhibitor compounds inhibit herpes simplex virus proliferation


FOR IMMEDIATE RELEASE
2021-11-19

Oncotarget published "Host targeted antiviral (HTA): functional inhibitor compounds of scaffold protein RACK1 inhibit herpes simplex virus proliferation" which reported that 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.

In addition, HIV-1 and Herpes Simplex virus are known to use IRES as well. 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.

Dr. Sivanesan Dakshanamurthy from The Georgetown University Medical Center, Dr. Qiyi Tang from The Howard University College of Medicine and Dr. Hemayet Ullah from Howard University 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."

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.

Unlike other infectious agents, viruses offer few intrinsic targets for inhibition by antiviral molecules [1]. With their simple structural form and their ability to hijack molecular machinery from host cells to complete their replication cycle, viruses evade most efforts to contain them [2]. However, as viruses require host factors to translate their transcripts, targeting the host factor offers a unique opportunity to develop novel antiviral drugs.

In this regard, identification of the ribosome localized host protein Receptor for Activated C Kinase 1 for viral Internal Ribosomal Entry Site -mediated translation of non-capped mRNAs has been established as a target for developing antiviral drugs [3, 4]. Indeed, many of the animal and human viruses containing IRESs are RNA viruses, and most of them belong only to three families of + ssRNA viruses.

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 Kaposi's sarcoma-associated herpesvirus [7–9], Epstein-Barr virus [10], herpes simplex virus [11], murine gammaherpesvirus 68 [12], Marek's disease virus [13], and simian vacuolating virus 40 [14]. In addition, presence of the IRES in double stranded DNA containing White Spot Syndrome virus, which is in the family Nimaviradae, is also reported [15]. WSSV is widely known as the causative pathogen of a serious disease in shrimp [15].

Figure 8: Efficacy of SD29-14 compared with anti-herpes drug acyclovir. (A) Hep-2 cells were incubated with the indicated compounds in the presence of HSV1-Luc virus at a concentration of 4 × 106 pfu/ml media. (B) Quantification of the luciferase signal from the samples in panel (A). Signals from three replicates from two separate experiments were combined to generate the average and the standard error bar.

One of the characteristics of HSV infection is its ability to latently infect neurons so that it can be reactivated, thereby causing recurrent infections [21]. Although the clinical symptoms of HSV-caused diseases can be controlled with antiviral drugs, these drugs are not strong enough to stop subclinical transmission [20, 22].

The Dakshanamurthy/Tang/Ullah Research Team concluded in their Oncotarget Research Output that this work will usher a new avenue to develop effective and durable drugs that can potentially circumvent the selection pressure induced drug-resistance scenarios. 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

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DOI - https://doi.org/10.18632/oncotarget.26907

Full text - https://www.oncotarget.com/article/26907/text/

Correspondence to - Sivanesan Dakshanamurthy - sd233@georgetown.edu, Qiyi Tang - qiyi.tang@howard.edu, and Hemayet Ullah - 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),

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