COVID-19: Characterizing post-translational modifications of SARS-CoV-2 for refining in silico drug identification models and directing host target selection for HTP anti-viral screening
EMSL Project ID
51600
Abstract
There are no effective vaccines or therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The absence of treatment and prevention options has resulted in a global pandemic with over 400k confirmed death and catastrophic economic impact around the world. Current clinical management of COVID-19, the disease associate with SARS-CoV-2, relies on symptom management. However, early viral sequencing has allowed for in silico screening of hundreds of thousands of small molecules for potential binding and inhibition of viral proteins. This technique utilizes structural inference based on RNA sequencing and previous resolved structures. These simulations can include theoretical expected post translational modifications (PTMs) to viral proteins. PTMs such as glycosylation, palmitoylation, ADP-ribosylation, and phosphorylation alter 3D structure and binding interactions between viral proteins and small molecules, as well as host proteins, and all these PTMs have been found on coronavirus proteins. In spite of massive in silico screening efforts, HTP in vitro screening of these hits have not resulted in candidate advancement. This challenge is largely due to the lack of basic understanding of SARS-CoV-2 itself and its interactions with host proteins that dictate the immune response. Despite the tremendous efforts by the scientific community, many questions remain unanswered. We propose to apply the state-of-the-art mass spectrometry capabilities at EMSL to map viral PTMs and determine the viral and host cell proteins interactions that are dependent on PTMs. Identifying SARS-CoV-2 PTMs will advance our mechanistic understanding of viral protein processing in virion production. However, this information has more immediate practical applications in the fight against COVID-19 such as refining in silico screening models with empirical data for more accurate mass screening of compound libraries as well as guiding pathway selection in host targeted drug screening. Viral and host protein interactions shape the immune response thereby influencing disease outcomes making defining SARS-CoV-2 PTMs critical to both drug and vaccine development.
Project Details
Project type
Limited Scope
Start Date
2020-09-01
End Date
2021-09-30
Status
Closed
Released Data Link
Team
Principal Investigator