Due to the rapidly spreading of novel coronavirus disease (COVID‐19) worldwide, there is an urgent need to develop efficient vaccines and specific antiviral treatments. Pathways of the viral entry into cells are interesting subjects for targeted therapy of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The present study aims to provide a systematic evaluation of the most recent in vitro and in vivo investigations targeting SARS‐CoV‐2 cell entry. A systematic search was carried out in major medical sources, including MEDLINE (through PubMed), Web of Science, Scopus, and EMBASE. Combinations of the following search terms were used: SARS‐CoV‐2, in vitro, in vivo, preclinical, targeted therapy, and cell entry. A modified version of the Consolidated Standards of Reporting Trials and Systematic Review Centre for Laboratory Animal Experimentation assessment tools were applied for evaluating the risk of bias of in vitro and in vivo studies, respectively. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure. A total of 2,649 articles were identified through searching PubMed, Web of Science, Scopus, EMBASE, Google Scholar, and Biorxiv. Finally, 22 studies (one in vivo study and 21 in vitro studies) were included. The spike (S) glycoprotein of the SARS‐CoV‐2 was the main target of investigation in 19 studies. SARS‐CoV‐2 can enter into the host cells through endocytosis or independently. SARS‐CoV‐2 S protein utilizes angiotensin‐converting enzyme 2 or CD147 as its cell‐surface receptor to attach host cells. It consists of S1 and S2 subunits. The S1 subunit mediates viral attachment to the host cells, while the S2 subunit facilitates virus‐host membrane fusion. The cleavage of the S1–S2 protein, which is required for the conformational changes of the S2 subunit and processing of viral fusion, is regulated by the host proteases, including cathepsin L (during endocytosis) and type II membrane serine protease (independently). Targeted therapy strategies against SARS‐CoV‐2 cell entry mechanisms fall into four main categories: strategies targeting virus receptors on the host, strategies neutralizing SARS‐CoV‐2 spike protein, strategies targeting virus fusion to host cells, and strategies targeting endosomal and non‐endosomal dependent pathways of virus entry. Inhibition of the viral entry by targeting host or virus‐related components remains the most potent strategy to prevent and treat COVID‐19. Further high‐quality investigations are needed to assess the efficacy of the proposed targets and develop specific antivirals against SARS‐CoV‐2.
