SARS‐CoV‐2–host proteome interactions for antiviral drug discovery
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 replica...
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Wiley
2021
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oai:doaj.org-article:c87ddbd7671244cc9c1ca8b5b5555d622021-11-29T08:21:36ZSARS‐CoV‐2–host proteome interactions for antiviral drug discovery1744-429210.15252/msb.202110396https://doaj.org/article/c87ddbd7671244cc9c1ca8b5b5555d622021-11-01T00:00:00Zhttps://doi.org/10.15252/msb.202110396https://doaj.org/toc/1744-4292Abstract 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.Xiaonan LiuSini HuuskonenTuomo LaitinenTaras RedchukMariia BogachevaKari SalokasIna PöhnerTiina ÖhmanArun Kumar TonduruAntti HassinenLisa GawriyskiSalla KeskitaloMaria K VartiainenVilja PietiäinenAntti PosoMarkku VarjosaloWileyarticledrug discoverymass spectrometryproteomicsSARS‐CoV‐2virus–host interactionsBiology (General)QH301-705.5Medicine (General)R5-920ENMolecular Systems Biology, Vol 17, Iss 11, Pp n/a-n/a (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
drug discovery mass spectrometry proteomics SARS‐CoV‐2 virus–host interactions Biology (General) QH301-705.5 Medicine (General) R5-920 |
| spellingShingle |
drug discovery mass spectrometry proteomics SARS‐CoV‐2 virus–host interactions Biology (General) QH301-705.5 Medicine (General) R5-920 Xiaonan Liu Sini Huuskonen Tuomo Laitinen Taras Redchuk Mariia Bogacheva Kari Salokas Ina Pöhner Tiina Öhman Arun Kumar Tonduru Antti Hassinen Lisa Gawriyski Salla Keskitalo Maria K Vartiainen Vilja Pietiäinen Antti Poso Markku Varjosalo SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| description |
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. |
| format |
article |
| author |
Xiaonan Liu Sini Huuskonen Tuomo Laitinen Taras Redchuk Mariia Bogacheva Kari Salokas Ina Pöhner Tiina Öhman Arun Kumar Tonduru Antti Hassinen Lisa Gawriyski Salla Keskitalo Maria K Vartiainen Vilja Pietiäinen Antti Poso Markku Varjosalo |
| author_facet |
Xiaonan Liu Sini Huuskonen Tuomo Laitinen Taras Redchuk Mariia Bogacheva Kari Salokas Ina Pöhner Tiina Öhman Arun Kumar Tonduru Antti Hassinen Lisa Gawriyski Salla Keskitalo Maria K Vartiainen Vilja Pietiäinen Antti Poso Markku Varjosalo |
| author_sort |
Xiaonan Liu |
| title |
SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| title_short |
SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| title_full |
SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| title_fullStr |
SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| title_full_unstemmed |
SARS‐CoV‐2–host proteome interactions for antiviral drug discovery |
| title_sort |
sars‐cov‐2–host proteome interactions for antiviral drug discovery |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/c87ddbd7671244cc9c1ca8b5b5555d62 |
| work_keys_str_mv |
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