Effect of dimeric netropsin analogue 15Lys-bis-Nt and acyclovir on the reproduction of herpes simplex virus type 1. The search for variants of herpes virus with drug resistance to 15Lys-bis-Nt and acyclovir

Андронова, В. Л.; Grokhovsky, S. L.; Surovaya, A. N.; Gursky, G. V.; Ga, Galegov

doi:10.1134/s1607672915010123

Cited by 1 publication

(1 citation statement)

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“…Viruses pose a constant threat for all living organisms and they constantly evolve to evade any anti-viral drugs that directly aim to their intrinsic targets. The clinically effective drugs acyclovir and valacyclovir [38] are available to treat HSV-caused diseases, but resistant to these drugs are reported [39]. HSV infection remains an important public health problem causing significant morbidity and mortality [40].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%