key: cord-0713221-xuqsskin
authors: Magro, Giuseppe
title: SARS-CoV-2 and COVID-19: What are our options? Where should we focus our attention on to find new drugs and strategies?
date: 2020-04-22
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2020.101685
sha: 3169e913b1cabd33f32605008ba5476437192a31
doc_id: 713221
cord_uid: xuqsskin

nan

since the outbreak of COVID-19 many efforts are being made to engineer new drugs and to find ways of fighting this pandemic. We write this letter to focus everybody's attention on the possible and viable strategies to find new drugs and therapeutic compounds. In doing so we describe the virus cycle of infection, showing for each phase a possible compound of therapeutic use.

This first phase consist of membrane interaction between the host cell and the virus, allowed by the ACE2 receptor. Cleavage and activation of SARRS-CoV spike protein (S) by a host cell protease is essential for viral entry, this host cell protease is called TMPRSS2. Potential in vitro proven inhibitor of TMPRSS2 is camostat mesylate 1 .

Endocytosis: This second phase allows the virus inside the host cell. One known regulator of endocytosis is the AP2-associated protein kinase 1(AAK1). Using Artificial Intelligence it was possible to find a good inhibitor of AAK1 like Baricitinib, a known Janus kinase inhibitor which can reduce both viral entry and inflammation in patients 2 . Another option in altering the endocytosis process is hydroxychloroquine, a derivate of chloroquine, which alters pH (by increasing it) of endosome and lysosome essential for membrane fusion between host cell and the virus. An in vitro experiment showed that in chloroquine treated cells endosomes vesicles were abnormally enlarged. This indicates an altered maturation process of endosomes, blocking endocytosis, resulting in failure of further transport of virions to the replication site 3 . promoter and facilitates its translocation from cytosol to nucleus. The N protein is essential for IL-6 secretion to happen, since deletion of the C-terminus of the N protein resulted in the loss of function in the activation of IL-6 5 .This shows how high levels of IL-6 are directly induced by SARS-CoV-2, besides being also associated with extensive lung injuries, making IL-6 a good therapeutic target, with drugs like Tocilizumab a known IL-6 inhibitor.

Targeting viral components such as the spike proteins of the virus with specific antibodies is another therapeutic option, this happens during free circulation of the virus.

Coronaviruses neutralizing antibodies usually target the spike proteins(S) on the viral surface of the virus which allow it to enter host cells. The S protein has two subunits: one that mediates cell binding S1, and one that mediates cell fusion, the S2 domain. The most neutralizing antibodies are shown to target the receptor interaction site in S1 subunit. The latest developed antibody showing neutralizing properties is the Human 47D11 antibody, which was shown to target the S1B receptor binding domain of SARS-S and SARS2-S. Despite its capacity to inhibit infected cells with SARS-S and SARS2-S, the binding activity did not compete with S1B to the ACE2 receptor. This seems to indicate that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through a yet unknown mechanism different from binding interference 6 .This study shows how, despite the high capability of the virus to mutate, targeting conserved core structure of the S1B receptor is a good strategy. This also provides evidence for the design of a SARS-CoV-2 vaccine composed of viral structural proteins, like the S proteins.

In conclusion we showed all phases of the virus cycle that can possibly be targeted, showing the most promising targets. We aimed to shed some light on the future drugs and therapies that need to be engineered in the future to come.

Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

COVID-19: combining antiviral and anti-inflammatory treatments. The Lancet Infectious Diseases

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-kappaB

A human monoclonal antibody blocking SARS-CoV-2 infection