Macrodomain Binding Compound MRS 2578 Inhibits Alphavirus Replication

Abstract

Alphaviruses are positive-strand RNA viruses causing febrile disease. Macrodomain-containing proteins, involved in ADP-ribose mediated signaling, are encoded by both host cells and several virus groups, including alphaviruses. In this study, compound MRS 2578 that targets the human MacroD1 protein inhibited Semliki Forest virus production as well as viral RNA replication and replicase protein expression. The inhibitor was similarly active in alphavirus trans -replication systems, indicating that it targets the viral RNA replication stage.

Intracellular mono-ADP-ribosyltransferases at the host–virus interphase

“…Finally, a recent study used compounds that were developed using in silico techniques to target MacroD1. Testing some of the compounds for their ability to interfere with Semliki Forest virus replication identified a compound with weak activity [ 256 ]. Together, these are promising studies that lay down the groundwork for developing much needed inhibitors of viral macrodomains.…”

Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target

“…Initial compounds targeting virus macrodomains have been described for alphaviruses , and coronaviruses. − These efforts have used both screening of compound libraries, ,, in crystallo fragment screening to discover early small inhibitors, and further development to produce more potent compounds. , The discovered SARS-CoV-2 Mac1 inhibitors have also been recently discussed in reviews. , The majority of the compounds reached low-mid μM potency, though a few reached sub-μM IC 50 ’s, and in general, they lacked the properties allowing cell permeability and subsequent validation of SARS-CoV-2 Mac1 as a pharmacological target.…”

Discovery of 2-amide-3-methylester thiophenes that target SARS-CoV-2 Mac1 and repress coronavirus replication, validating Mac1 as an anti-viral target

“…Therefore, SARS-CoV-2 Mac1 is an intriguing target for drug discovery and small molecule inhibitors might offer novel therapeutics to combat COVID-19. Initial compounds targeting virus macrodomains have been described for alphaviruses (Mattila et al, 2021;Li et al, 2017) and coronaviruses (Sherrill et al, 2022;Roy et al, 2022;Schuller et al, 2021;Gahbauer et al, 2023). These efforts have used both screening of compound libraries (Roy et al, 2022;Sowa et al, 2021;Dasovich et al, 2022), in crystallo fragment screening to discover early small inhibitors (Schuller et al, 2021) and further development to produce more potent compounds (Gahbauer et al, 2023;Sherrill et al, 2022).…”

“…These efforts have used both screening of compound libraries (Roy et al , 2022; Sowa et al , 2021; Dasovich et al , 2022), in crystallo fragment screening to discover early small inhibitors (Schuller et al , 2021) and further development to produce more potent compounds (Gahbauer et al , 2023; Sherrill et al , 2022). The majority of the compounds have reached low-mid µM potency, though a few have reach sub-µM IC 50 ’s (Mattila et al , 2021; Li et al , 2017)(Sherrill et al , 2022; Roy et al , 2022; Schuller et al , 2021; Gahbauer et al , 2023)(Roy et al , 2022; Sowa et al , 2021; Dasovich et al , 2022)(Schuller et al , 2021)(Gahbauer et al , 2023; Sherrill et al , 2022), and in general they have lacked the properties allowing cell permeability and subsequent validation of Mac1 as a pharmacological target.…”

“…Therefore, SARS-CoV-2 Mac1 is an intriguing target for drug discovery and small molecule inhibitors might offer novel therapeutics to combat COVID-19. Initial compounds targeting virus macrodomains have been described for alphaviruses 15,16 and coronaviruses [17][18][19][20] . These efforts have used both screening of compound libraries 18,21,22 , in crystallo fragment screening to discover early small inhibitors 19 and further development to produce more potent compounds 17,20 .…”