Therapeutic role of mTOR inhibitors in control of SARS-CoV-2 viral replication

Abstract

By the end of 2019, COVID-19 was reported in Wuhan city of China, and through human-human transmission, this virus spread worldwide and became a pandemic. Initial symptoms of the disease include fever, cough, loss of smell, taste, and shortness of breath, but a decrease in the oxygen levels in the body leads, and pneumonia may ultimately lead to the patient's death. However, the symptoms vary from patient to patient. To understand COVID-19 disease pathogenesis, researchers have tried to understand the cellular pathways that could be targeted to suppress viral replication. Thus, this article reviews the markers that could be targeted to inhibit viral replication by inhibiting the translational initiation complex/regulatory kinases and upregulating host autophagic flux that may lead to a reduction in the viral load. The article also highlights that mTOR inhibitors may act as potential inhibitors of viral replication. mTOR inhibitors such as metformin may inhibit the interaction of SARS-CoV-2 Nsp's and ORFs with mTORC1, LARP1, and 4E-BP. They may also increase autophagic flux by decreasing protein degradation via inhibition of Skp2, further promoting viral cell death. These events result in cell cycle arrest at G1 by p27, ultimately causing cell death.

Keywords: Autophagy; Coronavirus; Metformin; Skp2; mTOR inhibition.

Fig. 1

Protein-Protein interaction between the regulatory components of autophagy and endoplasmic reticulum-associated degradation (ERAD). Essential targets include BECN1 (Beclin1), SKP2 (S-phase kinase-associated protein 2), and USP10 (Ubiquitin Specific Peptidase 10) (STRING: Functional Protein Association Networks, n.d.)

Fig. 2

Potential replication mechanism of SARS-CoV-2 and its  modulation. Direct and Indirect Co-regulation of mTORC1 and Skp2 via Metformin enhances the autophagic flux and inhibits SARS-CoV-2 protein translational assembly by targeting LARP1, Nsps 1–6, Orf 3–10, and 4E-BP proteins

Fig. 3

Pictorial representation of molecular docking analysis. a Binding orientation in the docked complex of MET with FKPB7. b Binding orientation in the docked complex of MET with LARP1. The compound (MET (metformin)) is represented in green. Images were generated using Discovery Studio Visualizer

Fig. 4

Possible mechanism of enhanced SARS-CoV-2 infection through mTOR inhibition. mTOR inhibitors can hinder mTOR mediated TFEB phosphorylation resulting in nuclear translocation of TFEB. Nuclear TFEB activates the genes promoting lysosomal activities including microautophagy, an autophagy related pathway. Microautophagy induces degradation of membrane proteins such as IFITM2 and IFITM3 which in turn promotes the entry of SARS-CoV-2 into the cells by facilitating the fusion between viral and cell membrane