SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Molecular Systems Biology

Mariia Bogacheva¹  Vilja Pietiäinen¹  Antti Hassinen¹  Tiina Öhman²  Lisa Gawriyski²  Taras Redchuk²  Salla Keskitalo²  Xiaonan Liu²  Maria K Vartiainen²  Markku Varjosalo²  Sini Huuskonen²  Kari Salokas²  Antti Poso³  Ina Pöhner³  Tuomo Laitinen³  Arun Kumar Tonduru³ 

[1] Helsinki Institute of Life Science University of Helsinki Helsinki Finland;Institute of Biotechnology University of Helsinki Helsinki Finland;School of Pharmacy University of Eastern Finland Kuopio Finland;

关键词: drug discovery;    mass spectrometry;    proteomics;    SARS‐CoV‐2;    virus–host interactions;   

DOI  :  10.15252/msb.202110396

来源: DOAJ

【 摘 要 】

Abstract Treatment options for COVID‐19, caused by SARS‐CoV‐2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS‐CoV‐2–host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS‐CoV‐2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP‐MS) and the complementary proximity‐based labeling MS method (BioID‐MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS‐CoV‐2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image‐based drug screen with infectious SARS‐CoV‐2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein–protein interactions.

【 授权许可】

Unknown