B2: Protein de-ADP-ribosylation und NMPylation activities as potential therapeutic targets against coronaviruses

Project description:

Coronaviruses are important human and animal pathogens. They are mainly associated with respiratory and intestinal infections and have significant zoonotic potential, resulting in several outbreaks of severe respiratory infections in humans over the past 2 decades including the SARS-CoV-2 pandemic starting in 2019. Therapeutic options to treat severe forms of COVID-19 and other coronavirus infections are very limited, indicating a high priority for the development of novel antiviral drugs. To address this need, project B2 focuses on two coronaviral proteins that are conserved among all coronaviruses: the coronavirus macrodomain (macD) in nonstructural protein 3 (nsp3) and the recently discovered nucleotidyltransferase (NiRAN) which is linked to the viral RNA-dependent RNA polymerase domain in nsp12 and was recently shown to be essential for coronavirus replication.

Coronavirus replicase polyprotein 1ab. Proteolytic processing by two or three viral proteases (PL, 3CL) results in the release of up to 16 nonstructural proteins (nsp) with numerous enzymatic and other functions.

Scientific goal:

The project aims to comprehensively characterize the biochemical properties of two coronavirus proteins/enzymes (macD, NiRAN) and their functions in the viral replication cycle using appropriate cell culture systems. Based on the conserved substrate specificity of the NiRAN domain, HTS assays will be developed and used to identify potential inhibitors.

DRUID Collaboration partners:

A2 Grünweller, A3 Weber, C5 Kraiczy, E3 Rahlfs/Przyborski

References B2: 1. *Slanina et al. (2021) Proc Natl Acad Sci USA 118: e2022310118 2. *Krichel et al. (2021) Sci. Adv. 7: eabf1004  3. *Müller et al. (2021) Antiviral Res 175: 1004706 4. *Snijder et al. (2016) Adv Virus Res 96: 59-126 5. *Putics et al. (2005) J Virol 79: 12721-31.