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Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.<\/jats:p>","DOI":"10.3389\/fmolb.2021.725528","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T17:19:06Z","timestamp":1630689546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":64,"title":["Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza"],"prefix":"10.3389","volume":"8","author":[{"given":"Yalda","family":"Rahbar Saadat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Mahdi","family":"Hosseiniyan Khatibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sepideh","family":"Zununi Vahed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammadreza","family":"Ardalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,30]]},"reference":[{"key":"B1","first-page":"1686","article-title":"Catalytic Cleavage of the Androgen-Regulated TMPRSS2 Protease Results in its Secretion by Prostate and Prostate Cancer Epithelia","volume":"61","author":"Afar","year":"2001","journal-title":"Cancer Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1007\/s40256-020-00438-6","article-title":"Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections","volume":"20","author":"Al-Horani","year":"2020","journal-title":"Am. 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