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SARS-CoV-2\u00a0has infected more than 111 million people worldwide and caused over 2.47 million deaths. Individuals infected with SARS-CoV-2 show symptoms of fever, cough, dyspnea, and fatigue with severe cases that can develop into pneumonia, myocarditis, acute respiratory distress syndrome, hypercoagulability, and even multi-organ failure.  Current\u00a0clinical management consists largely of supportive care as commonly administered treatments, including convalescent plasma, remdesivir, and high-dose glucocorticoids. These have demonstrated  modest benefits in a small subset of hospitalized patients, with only dexamethasone showing demonstrable efficacy in reducing mortality and length of hospitalization. At this time, no SARS-CoV-2-specific antiviral drugs are available,\u00a0although\u00a0several\u00a0vaccines\u00a0have been approved for use in recent months. In this review, we will evaluate the efficacy\u00a0of preclinical and clinical drugs that precisely target three different, essential steps of the SARS-CoV-2 replication cycle: the spike protein during entry, main protease (M\n                    <jats:sup>Pro<\/jats:sup>\n                    ) during proteolytic activation, and RNA-dependent RNA polymerase (RdRp) during transcription. We will assess the advantages and limitations of drugs that precisely target evolutionarily well-conserved domains, which are less likely to mutate, and therefore less likely to escape the effects of these drugs. We propose that a multi-drug cocktail  targeting\u00a0precise proteins,\u00a0critical to the  viral replication cycle, such as spike protein, M\n                    <jats:sup>Pro<\/jats:sup>\n                    , and RdRp, will be the most effective\u00a0strategy of  inhibiting SARS-CoV-2 replication and limiting its spread in the general population.\n                  <\/jats:p>","DOI":"10.1186\/s12985-021-01526-y","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T08:02:31Z","timestamp":1617004951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Precision therapeutic targets for COVID-19"],"prefix":"10.1186","volume":"18","author":[{"given":"Zachary A.","family":"Krumm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connor P.","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lith H.","family":"Nasif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duane A.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd E.","family":"Golde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2992-4234","authenticated-orcid":false,"given":"Benoit I.","family":"Giasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"1526_CR1","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","volume":"579","author":"F Wu","year":"2020","unstructured":"Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. 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