Abstract: REVIEW published: 30 March 2021 doi: 10.3389/fimmu.2021.663586 Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities Zena Wehbe 1†, Maya Wehbe 2†, Rabah Iratni 3, Gianfranco Pintus 4,5, Hassan Zaraket 6,7, Hadi M. Yassine 8* and Ali H. Eid 9,10* Edited by: Shuofeng Yuan, The University of Hong Kong, Hong Kong Reviewed by: Jun Wang, University of Arizona, United States Shailesh Kumar Patel, Chhattisgarh Kamdhenu Vishwavidyalaya, India *Correspondence: Hadi M. Yassine hyassine@qu.edu.qa Ali H. Eid ali.eid@qu.edu.qa † These authors have contributed equally to this work Specialty section: This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology Received: 03 February 2021 Accepted: 15 March 2021 Published: 30 March 2021 Citation: Wehbe Z, Wehbe M, Iratni R, Pintus G, Zaraket H, Yassine HM and Eid AH (2021) Repurposing Ivermectin for COVID-19: Molecular Aspects and Therapeutic Possibilities. Front. Immunol. 12:663586. doi: 10.3389/fimmu.2021.663586 1 Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon, 2 Department of Internal Medicine, Basingstoke & North Hampshire Hospital, Basingstoke, United Kingdom, 3 Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates, 4 Department of Medical Laboratory Sciences, College of Health Sciences, and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates, 5 Department of Biomedical Sciences, University of Sassari, Sassari, Italy, 6 Department of Experimental Pathology, Immunology and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, 7 Center for Infectious Disease Research (CIDR), Faculty of Medicine, American University of Beirut, Beirut, Lebanon, 8 Biomedical Research Center, Q.U. Health, Qatar University, Doha, Qatar, 9 Department of Basic Medical Sciences, College of Medicine, Q.U. Health, Qatar University, Doha, Qatar, 10 Biomedical and Pharmaceutical Research Unit, Q.U. Health, Qatar University, Doha, Qatar As of January 2021, SARS-CoV-2 has killed over 2 million individuals across the world. As such, there is an urgent need for vaccines and therapeutics to reduce the burden of COVID-19. Several vaccines, including mRNA, vector-based vaccines, and inactivated vaccines, have been approved for emergency use in various countries. However, the slow roll-out of vaccines and insufficient global supply remains a challenge to turn the tide of the pandemic. Moreover, vaccines are important tools for preventing the disease but therapeutic tools to treat patients are also needed. As such, since the beginning of the pandemic, repurposed FDA-approved drugs have been sought as potential therapeutic options for COVID-19 due to their known safety profiles and potential anti-viral effects. One of these drugs is ivermectin (IVM), an antiparasitic drug created in the 1970s. IVM later exerted antiviral activity against various viruses including SARS-CoV-2. In this review, we delineate the story of how this antiparasitic drug was eventually identified as a potential treatment option for COVID-19. We review SARS-CoV-2 lifecycle, the role of the nucleocapsid protein, the turning points in past research that provided initial ‘hints’ for IVM’s antiviral activity and its molecular mechanism of action- and finally, we culminate with the current clinical findings. Keywords: COVID-19,..