The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy

Abstract

In late 2019, a new member of the Coronaviridae family, officially designated as “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2), emerged and spread rapidly. The Coronavirus Disease-19 (COVID-19) outbreak was accompanied by a high rate of morbidity and mortality worldwide and was declared a pandemic by the World Health Organization in March 2020. Within the Coronaviridae family, SARS-CoV-2 is considered to be the third most highly pathogenic virus that infects humans, following the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Four major mechanisms are thought to be involved in COVID-19 pathogenesis, including the activation of the renin-angiotensin system (RAS) signaling pathway, oxidative stress and cell death, cytokine storm, and endothelial dysfunction. Following virus entry and RAS activation, acute respiratory distress syndrome develops with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In this review, blockers of angiotensin II receptor and/or PARP, PARG, and TRPM2, including vitamin D3, trehalose, tannins, flufenamic and mefenamic acid, and losartan, have been investigated for inhibiting RAS activation and quenching oxidative burst. Moreover, the application of organic and inorganic nanoparticles, including liposomes, dendrimers, quantum dots, and iron oxides, as therapeutic agents for SARS-CoV-2 were fully reviewed. In the present review, the clinical manifestations of COVID-19 are explained by focusing on molecular mechanisms. Potential therapeutic targets, including the RAS signaling pathway, PARP, PARG, and TRPM2, are also discussed in depth.

Integration of omics data to generate and analyse COVID-19 specific genome-scale metabolic models

“…However, all studies agree that the lack of randomised controlled studies, small cohorts, different dosages and vitamin D formulations, non-standardised study conditions and large heterogeneity between the studies hinders the evaluation and conclusions. Especially since studies in preclinical models showed that vitamin D3 inhibits SARS-CoV-2 virus replication in cells [ 69 , 70 ], but affect also other aspects of COVID-19 disease [ 71 ]. Additionally, the analysis of tINIT models proposed that the metabolism of vitamin D3 molecules is changed in different cell types and this could affect the efficacy and availability of vitamin D3 in the body.…”

Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients

“…In ARDS and COPD associated with COVID-19, the hypoxic conditions result in inflammation that may lead to OS. Increased OS leads, as a consequence, to a decrease in nitric oxide (NO) release mainly because ROS interfere with the activity of the NO synthases and cause an inadequate production of tetrahydrobiopterin [54]. Optimal concentrations of O 2 are required for the synthesis of NO by the nitric oxide synthases.…”

“…Moreover, decreased NO following an oxidative burst can stimulate the production of metalloproteinases-2 and -9 that contribute to pulmonary damage [55]. Hypoxia also increases the presence of protons, in a similar way as in a neutral or acidic pH, compromising the stability of ONOO − and decomposing peroxynitrous acid to form nitrates (NO 3 − ) and NO 2 − [54]. ONOO − causes the irreversible process of nitration of tyrosines in proteins, it oxidizes the thiol groups in them [56] and it also lowers the H 2 S concentration.…”

Antibacterial and antiviral high-performance nanosystems to mitigate new SARS-CoV-2 variants of concern

“…Although prevalent for a few decades now, nanotechnology has found new relevance in healthcare in the present scenario when COVID-19 controlling and managing pre/post infection consequences are the main priority of health agencies and experts, as illustrated in Figure 1 B. [ [14] , [15] , [16] ].

Figure 1 A) Prospective of NSs-supported approaches and strategies to mitigate COVID-19 viral infections caused by new SARS-CoV-2 variants of concerns (A), Illustration of state-of-art nanosytem investigated for diagnorics, treatment and vaccine delivery to manage COVID-19 efficient (B, Copyright ACS 2021 ).

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