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

• Published in: Molecular systems biology 2021-11, Vol.17 (11), p.1-n/a
• Main Authors: Liu, Xiaonan, Huuskonen, Sini, Laitinen, Tuomo, Redchuk, Taras, Bogacheva, Mariia, Salokas, Kari, Pöhner, Ina, Öhman, Tiina, Tonduru, Arun Kumar, Hassinen, Antti, Gawriyski, Lisa, Keskitalo, Salla, Vartiainen, Maria K, Pietiäinen, Vilja, Poso, Antti, Varjosalo, Markku
• Format: Article
• Language: English
• Subjects: Antiviral activity; Antiviral agents; Baits; Clinical trials; Cofactors; Coronaviruses; COVID-19; COVID-19 vaccines; Datasets; Drug development; drug discovery; Drug screening; Drugs; EMBO08; EMBO23; EMBO56; FDA approval; Genomes; Infections; Mass spectrometry; Mass spectroscopy; Methotrexate; Pathogenesis; Protein interaction; Proteins; Proteomes; proteomics; Replication; SARS‐CoV‐2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Viral infections; Viruses; virus–host interactions
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.202110396

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. Synopsis A large‐scale proteomics study identifies critical host proteins for SARS‐CoV‐2 processing. Proteins from these core subnetworks are used for drug repurposing analyses, indicating drugs with antiviral effects. A large‐scale proteomics study identifies 4,781 unique high‐confidence virus‐host protein‐protein interactions (PPIs) using 29 viral ORFs, and 4,362 unique PPIs for 18 suggested receptors/proteases/cofactors for SARS‐CoV‐2. The characterization of 693 hub proteins that connect viral baits and host baits via a dense network reveals critical host pathways used for viral replication. 59 compounds are prioritized that could be repurposed for 15 host protein targets used by the SARS‐CoV‐2 during the infection. Ten candidate drugs are validated using an image‐based drug screen assay, six of them demonstrating ant