key: cord-317240-d7ioosi6
authors: Shah, Niyati; Davariya, Vipul; Gupta, Sanjeev K.; Gajjar, Pankaj; Parmar, Jitendra; D'Cruz, Lancelot
title: Review: An insight into coronaviruses: Challenges, security and scope
date: 2020-08-04
journal: Rev Med Virol
DOI: 10.1002/rmv.2138
sha: 
doc_id: 317240
cord_uid: d7ioosi6

SARS‐CoV2 is a novel coronavirus; the seventh of its species to infect humans. The spread of this virus emerged in Wuhan, China in late December, 2019. Since then, this virus has spread to more than 200 countries and has caused a worldwide pandemic. Being a new species of coronaviruses, any cure or vaccines for this virus has not yet been obtained. A large amount of scientific studies and clinical trials are being carried out across the world to find a potential vaccine for this virus. Current work reports a review of potential drugs and vaccines that may be effective against this virus. Different scientific therapies that may potentially be effective against the SARS‐CoV2 virus are also reviewed. The mechanisms of various drugs, their efficiency in various clinical trials and their side effects are also studied.

virus also has a 96% similarity to a bat coronavirus and hence it is suspected that it most likely originated from bats. It is transmitted between humans by contact via respiratory droplets or fluids ejected while coughing or sneezing. Secondary infections also occur when there is a contact with inanimate surfaces contaminated with the virus.

Given the lack of approved drugs for the SARS-CoV-2 virus, it is essential to evaluate pre-existing drugs for activity. In principle, a molecule can act as an anti-viral drug if it inhibits some stage of the virus replication cycle, without being too toxic to the body cells. The possible modes of action of anti-viral agents would include being able to-. 

On 20th March, WHO 10 ritonavir and lopinavir and this mixture with interferon-beta. To get robust results, WHO 10 remarks that several thousands of patients will have to be recruited all across the world. A global data safety monitoring board will closely inspect results repeatedly and conclude whether any of these drugs have proven effect (or not, in which case trials for that drug may be dropped) or more drugs need to be added to the trial.

Remdesivir 10, 11 is an adenosine analogue originally tested against Ebola and some related viruses during the Ebola outbreak in the F I G U R E 1 3-D model 6 13 is not specifically designed to target SARS-CoV-2. As of 22nd March, two patients 10 in the United States of America were administered remdesivir and both of them showed improved conditions. Such individual-case evidences do not prove that this drug is efficient and safe for use; yet scientists do believe this drug has the best potential in clinical trials owing to the fact that even high doses of this compound does not cause toxicities.

According to the study results 14, 15 prematurely posted by the WHO on it's website by accident, the Chinese clinical trial on this drug was unsuccessful. The trial included 237 patients out of which 158 were administered remdesivir and the remaining 79 were given placebo. After a month of observations, results showed that 13.9% of the patients administered remdesivir died whereas the patients given placebo had a mortality rate of 12.8%. This drug was proven to be ineffective in curing Covid-19 patients in this trial. However, in the first clinical trial to evaluate an experimental drug in the United States by NIH, 16 this drug was proven to be effective. This trial was a randomized controlled trial involving 1063 patients. Out of these, one group of patients was administered remdesivir and the other group received placebo. According to the preliminary results, patients receiving remdesivir showed 31% faster recovery rates than the other group. The median recovery time for patients receiving remdesivir was 11 days, while that for the patients given placebo was 15 days. Results also showed improved survival rates. The remdesivir group had a mortality rate of 8% while the placebo group had a rate of 11.6%.

Another trial 17,18 on this drug was performed, which included 61 patients. Out of these, the data of 8 patients could not be analyzed F I G U R E 2 A general mechanism of viral replication in host cells and functions of inhibitors at various stages during the process. The virus first binds with the receptor of the host. A drug which is designed to be a fusion inhibitor will function at this stage by preventing the virus from binding with the receptor. Then, the virus will penetrate into the cell cytoplasm of the host. It undergoes uncoating at this stage. An amantadine inhibitor targets this stage and prevents uncoating. The viral RNA then transforms into a viral DNA. A reverse transciptase inhibitor works at this stage and prevents the viral DNA from being formed. The viral DNA then brings changes in the amino acid sequence of the host DNA and inserts itself in the sequencing. An integrase inhibitor prevents the virus from changing this sequence. With this, we get viral genomic RNA and viral mRNA. A protease inhibitor functions at this stage and prevents viral replication by selectively binding to viral proteases (eg, HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particle. The neuraminidase inhibitor targets this stage and prevents the virus from replicating, hence, preventing its reproduction by budding from the host cell. After this stage, the mature virus replicates itself and viral infection occurs. Image created with https://biorender.com/ and the results from analysis of data of the remaining 53 patients were published. These patients were administered remdesivir for 10 days and a median follow up of 18 days showed that 68% patients had improvements in oxygen support class. 47% patients were discharged and 13% died. The mortality rates in patients receiving invasive ventilation were found to be 18% while the rates in patients not receiving invasive ventilation was 5%. This trial reported reduced mortality rates and also clinical improvements in 68% of the patients by the use of remdesivir.

Chloroquine 11,13 is an anti-malarial and autoimmune disease drug and has been in use for the past 70 years. It appears to act by preventing viruses from binding to human cells. As these drugs are weak bases, they work by decreasing the acidity in endosomes. They prevent viral infection by increasing the endosornal pH required by the virus to enter the cell and also by interfering with the receptors of the virus.

Chloroquine phosphate is widely available, but has side effects, including headaches, diarrhea, rashes, itching and muscle problems like muscle pain and weakness. In cell culture, chloroquine shows activity against the SARS-CoV-2 virus, but the dosage requirements are usually high which may lead to serious toxicities if administered to humans. In rare cases, this drug affects the heart muscle which may lead to heart failure. Cases 19,20 of chloroquine poisoning have been reported in Nigeria. In the USA, 21 a man and his wife reportedly fell critically ill after self-medication with chloroquine phosphate derived from a fish tank cleaner where it is used as an additive. The man later died and his wife was placed in critical care.

Hydroxychloroquine also has activity 19 

The ritonavir and lopinavir combination 10 showed no significant difference between the two groups. Mortality at 28 days was found to be same in both the groups. However, doctors commented that all trial patients were critically ill (with more than one fifth of them dying) and the drugs may have been given too late.

If administered at earlier stages of viral infection, these drugs may be more effective. Though these drugs are usually safe, while curing critically ill patients, they may interact with other drugs administered to them and could possibly cause significant liver damage.

Interferon-beta 10 is a molecule involved in regulating body inflammation and has been proven effective 27 

This is designed to target RNA viruses including influenza viruses, 

Another potential therapy 13 Also, administering antibodies may suppress the patient's natural immune system leaving them at risk of re-infection. Presently, we face a lot of unknowns in this therapy. We do not know the exact dosage of antibodies needed to be administered, we do not know at which stage of infection this therapy should be given so that results are most efficient and we also do not know the age-group of patients this will this benefit most. Doctors also remark that the patients who have been previously treated using this therapy and shown improved conditions had also received antiviral drugs and hence, it is hard to precisely determine the effect of this therapy. As sample sizes in convalescent plasma trials are small, we need to carry out more vigorous studies and trials to know the exact efficiency of this therapy.

Wu 42 has suggested a mechanism for a potential therapy for SARS-CoV-2 induced lung injury which is based on the idea of balancing the renin-angiotensin system (RAS). Here, the activation of the RAS cascade involves renin. Renin cleaves angiotensinogen to generate a decapeptide hormone (Ang I), which is then converted to an octapeptide hormone (Ang II) by angiotensin-converting enzyme (ACE). It binds to its receptors (AT1 is angiotensin II type I and AT2 is angiotensin II type II) which results in vasoconstriction and promotion of the release of aldosterone. ACE2 is a homologue 43 of ACE and plays a pivotal role of a counter-regulatory enzyme, for balancing responses initiated from ACE. Furthermore, ACE2 hydrolyses Ang I and Ang II to generate Ang-(1-9) and Ang-(1-7). Ang-(1-7) binds to the MAS receptor for antagonizing Ang II-mediated actions. SARS-CoV uses ACE2 as the entry receptor and we make an assumption that SARS-CoV-2 functions by the same mechanism. In mouse models 44 of SARS-CoV, ACE2 has been observed to be reduced by viral replication and viral spike protein, but not ACE. Inhibition of ACE2 expression or down-regulation of surface ACE2 by these coronaviruses may disrupt function balances between ACE/ACE2 and Ang II/Ang-(1-7), leading to lung injuries. From this, we can conclude that by compensation of ACE2 and maintenance of balance between ACE/ACE2, we may be able to stop severe lung injuries occurring due to SARS-CoV-2. At present, this approach yet awaits clinical trials to determine its efficiency. 45 4 | CONCLUSIONS 

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The authors declare that they have no conflicts of interest.

https://orcid.org/0000-0002-3060-2104Pankaj Gajjar https://orcid.org/0000-0002-5011-4757