Novel antiviral compound with unusual mechanism of action found to work well for HHV-6A and CMV

In a study led by Manfred Marschall German investigators analyzed the potency of novel pyrrolopyridine-class compounds and found one that is highly active against CMV and HHV-6A. It works at an early stage of viral protein production, and differs from ganciclovir in mechanism.

Professor Manfred Marschall, PhD, Universität Erlangen-Nürnberg

Based on its unique biological structure, pyrrolopyridine is known to be useful as an anti-cancer and therapeutic agent through its ability to act as a non-selective kinase inhibitor due to its structural similarity to ATP as well as a cell growth suppressor (El-Gamal 2017; Weir 2017; Hart 2015).

In a recent study, Friedrich Hahn and his colleagues aimed at analyzing the potency of novel pyrrolopyridine-class compounds in vitro as a herpesvirus antiviral.  There have been no published work on pyrrolopyridine analogs in the context of herpesviruses, except for pyrrolopyrimidine. This research synthesized and utilized SC88941 and its derivatives, SC105889 (amide-containing derivative) and SC106455.

𝛽-herpesviruses, especially HCMV and HHV-6A, were shown to have clear sensitivity to SC88941 as no cytotoxicity was noted at concentrations up to 10 µM, while the lack of viral drug resistance was observed through single step analysis in contrast to current therapy options. SC105889, a SC88941 derivative with terminal linker-coupled immobilization, proved to be extremely potent as well, indicating that the carbamate-linked variant is useful for protein binding studies. The study observed the means of SC88941 inhibitory activity of HCMV protein production through Western Blot and qPCR analysis.

The Western Blot analysis demonstrated that both SC88941 and GCV had no effect on immediate early protein (IE1p72) expression, but GCV and SC88941 had inhibited early (pUL44) and late protein (pp28) expression for 48 and 72 hours post-infection respectively. In addition, qPCR analysis stipulated the decreasing number of HCMV major intermediate early DNA copies with increasing concentrations of SC88941. The study also identified the target proteins of SC88941 as RNA and DNA binding proteins through a mass spectrometry-based proteomic analysis based on linker-coupled model SC88941 derivative compound, SC106455. Identification of these target proteins suggested SC88941 targets proteins associated with gene regulation, viral genome synthesis, and nucleic acid metabolism. This was visually confirmed under a laser-scanning microscopy as SC88941 had an inhibitory effect on the intracellular localization of viral proteins (pUL44, pp65, and viral major capsid protein) integral to viral expression.

The authors conclude that due to the low cytotoxicity and lack of drug resistance, SC88941 has promise as an antiviral therapy targeting integral proteins pertinent to early-late stage of viral replication through a complex mechanism in vitro.

Current therapy options for HHV-6 include three drugs approved drugs for CMV all viral DNA polymerase inhibitors: ganciclovir/valganciclovir, foscarnet, and cidofovir. Due to toxicity and viral drug resistance there is a strong interest in alternative therapy.

Read the full paper: Hahn 2018