Fig. 1.
SARS-CoV-2 replication. The viral cycle begins with the interaction between the viral spike and the cellular receptor. Several membrane proteins have been proposed as possible receptors for SARS-CoV-2; however, ACE2 is likely to be the most important one [10]. After the viral spike has interacted with the receptor, the virus gains entry into the host cytosol by two mechanisms: (1) by late endocytosis, releasing the viral RNA after the fusion with the lysosome (this entry is blocked by HCQ), or (2) by early endocytosis by fusion of the viral and host membrane without the participation of the lysosome. In these early stages, the priming processing by cellular proteases is the key for the exposure of the viral fusion motive. TMPRSS2 could act in both early and late endosome entry processes and could be inhibited by benzoic acid derivatives such as nafamostat, camostat, and bromhexine [18, 21]. Furthermore, other proteases such as cathepsin B could mediate the entry in the late lysosomal pathway, while only TMPRSS2 has been related to the early entry endosome [11, 13, 15, 18]. After fusion has occurred, the viral RNA is released into the cytoplasm and open reading frame 1 (ORF1) is translated to produce the RdRp. Subgenomic mRNAs are produced by discontinuous transcription, a process characteristic of this RdRp, which favors recombination. Compounds such as remdesivir, favipiravir, and sofosbuvir block this enzyme [39, 40, 41, 45]. The subgenomic mRNAs are then translated into protein. The genome has eight ORFs. The gene segments that encode nonstructural polyproteins are processed first and translated into ORF1a and ORF1b producing pp1a and pp1ab proteins, respectively. Protein pp1a and pp1ab are cleaved by the viral proteases (3CLpro and PLpro). The main protease is also the target of protease inhibitors such as lopinavir/ritonavir [7]. The structural proteins − spike, envelope, and membrane proteins − enter into the endoplasmic reticulum/Golgi complexes. Then, the nucleoprotein combines with the (+) strand genomic RNA (nucleoprotein complex) and merges with the other structural proteins in the endoplasmic reticulum-Golgi apparatus compartment [64]. Finally, the virion is excreted to the extracellular region through the exosomal pathway [64]. HCQ, hydroxychloroquine; RdRp, RNA-dependent RNA polymerase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2; ORF, open reading frame.