Classification of the present pharmaceutical agents based on the possible effective mechanism on the COVID-19 infection

Abstract

Objectives: There are several types of research on the COVID-19 disease which have been conducting. It seems that prevailing over the pandemic would be achieved only by mastering over the virus pathophysiology. We tried to categorize the massive amount of available information for useful interpretation.

Evidence acquisition: We searched databases with different keywords and search strategies that focus on virulence and pathophysiology of COVID-19. The present review has aimed to gather and categorize all implemented drugs based on the susceptible virulence mechanisms, and the pathophysiological events in the host cells, discussing and suggesting treatments.

Results: As a result, the COVID-19 lifecycle were categorized as following steps: "Host Cell Attachment" which is mainly conducted with ACE₂ receptors and TMPRSS2 from the host cell and Spike (S) protein, "Endocytosis Pathway" which is performed mainly by clathrin-mediated endocytosis, and "Viral Replication" which contains translation and replication of RNA viral genome. The virus pathogenicity is continued by "Inflammatory Reactions" which mainly caused moderate to severe COVID-19 disease. Besides, the possible effective therapeutics' mechanism and the pharmaceutical agents that had at least one experience as a preclinical or clinical study on COVID-19 were clearly defined.

Conclusion: The treatment protocol would be occasional based on the stage of the infection and the patient situation. The cocktail of medicines, which could affect almost all mentioned stages of COVID-19 disease, might be vital for patients with severe phenomena. The classification of the possible mechanism of medicines based on COVID-19 pathogenicity.

Keywords: COVID-19; Coronaviruses; Drug classification; Pandemic; Pharmaceutical agents; Possible treatments; SARS-CoV-2.

The classification of the possible mechanism of medicines based on COVID-19 pathogenicity

Fig. 1

Host Cell Attachment, The COVID-19 structural proteins include envelope (E), membrane (M), Spike (S), and nucleocapsid (N) proteins. S proteins bind the ACE₂ (angiotensin-converting enzyme-2) receptors with S₁ (subunit 1). The activity of proteases such as TMPRSS2 (transmembrane protease serine-2) has a crucial role in this step. The clathrin proteins, PICALM (phosphatidylinositol binding clathrin assembly protein) and S₂ (subunit 2) would participate in the next stage of the virus life cycle. The pharmaceutical agents which could interrupt the COVID-19 binding to the host cell membrane are exhibited in yellow color based on the mechanism and the specific site of action

Fig. 2

Endocytosis Pathway, This step initiates by viral particles clathrin-dependent endocytosis. The virus particles are now cargoes in the “Early Endosome.” Some proteins, like PICALM (phosphatidylinositol binding clathrin assembly protein), are essential for maturation of early endosome, especially its curvature and regulation of clathrin-dependent endocytosis rate. The “Late Endosome” is created by excluding the membrane receptors such as ACE₂ (angiotensin-converting enzyme-2) from the early endosome. Then lysosome is fused to late endosome for starting pH-dependent degradation. The lysosomal function needs acidic pH for injecting the viral genome into the host cell. FURIN proteases such as Cathepsin B & L are responsible for cutting Spike into S₁ and S₂ subunits from the FURIN cleavage site. After cutting the S₂ and revealing the S₁ subunit, the viral membrane could fuse the Late Endosome membrane and release the nucleocapsid protein into the host cell. The pharmaceutical agents which could interrupt the COVID-19 endocytosis pathway are exhibited in yellow color based on the mechanism and the specific site of action

Fig. 3

Viral Replication, COVID-19 disassemble to release the RNA genome after the intra-cellular entrance. The genome which contains 5ʹ-methylated caps and 3ʹ-polyadenylated tails is arranged in the order of 5ʹ. The open reading frames (ORFs) are translated into polyproteins in the cytoplasm. The produced polyproteins are cleaved by papain-like proteinase and 3C-like proteinase to produce sixteen non-structural proteins (NSP1-NSP16), which develop RNA Replication-Transcription Complex. The virus RNA replication is conducted by a viral enzyme called RNA-dependent RNA polymerase (RdRp) in the double-membrane vesicles (DMV) which is derived from the endoplasmic reticulum (ER). Then the genomic RNAs are transcribed into subgenomic RNAs and translated. As a result, structural proteins are synthesized and assembled into the nucleocapsid and viral envelope with ER-Golgi coordination. FURIN-like enzymes form the bound between S₁ and S₂ subunit in the assembling stage in the Golgi. Finally, the new virions are released by exocytosis into the extracellular compartment. The pharmaceutical agents which could interrupt the COVID-19 replication are exhibited in yellow color based on the mechanism and the specific site of action. +: positive-stranded RNA, −: negative-stranded RNA