Current and Future Challenges In Drug Therapeutics for Sars-Cov-2 Infection in Covid-19 Pandemic

Pneumonia of unknown cause detected in Wuhan; China was first reported to the WHO Country Office in China on December 31 2019. Later, the causative agent of which was identified to be Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On March 11, 2020, the pandemic caused by the SARS-CoV-2 was termed as COVID-19 by the World Health Organization (WHO), with the disease touching practically every country in the world. The SARSCoV-2 infection is, although characterized by flu-like symptoms, the fast progression is attributed to the acute respiratory distress syndrome (ARDS) [1] or myocarditis [2]. Many other manifestations of the disease have been described in different patient groups across different countries. As of June 18, 2020 the total infections globally stand at 8,242, 999 million people, with 445, 535 deaths, 4,530,266 recoveries. The take-home message is that despite the severity, there are more recoveries.


Introduction
Pneumonia of unknown cause detected in Wuhan; China was first reported to the WHO Country Office in China on December 31 2019. Later, the causative agent of which was identified to be Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On March 11, 2020, the pandemic caused by the SARS-CoV-2 was termed as COVID-19 by the World Health Organization (WHO), with the disease touching practically every country in the world. The SARS-CoV-2 infection is, although characterized by flu-like symptoms, the fast progression is attributed to the acute respiratory distress syndrome (ARDS) [1] or myocarditis [2]. Many other manifestations of the disease have been described in different patient groups across different countries. As of June 18, 2020 the total infections globally stand at 8,242, 999 million people, with 445, 535 deaths, 4,530,266 recoveries. The take-home message is that despite the severity, there are more recoveries.
As the researchers and pharmaceutical companies race to develop vaccines and antivirals, there is a lack of approved treatments for Coronavirus infections. Noteworthy is that most drugs or vaccine approaches that are touted to be useful have not been created taking SARS-CoV-2 in mind, but are being repurposed because of urgency. As a consequence, there is an unmet and urgent need for effective therapeutics, specifically against SARS-CoV-19 (WHO update, May 2020) [3].  The SARS-CoV-2 sequence appears to be closely related to that of SARS-CoV-1 that caused the SARS epidemic in 2003. Thus, what we know of SARS-CoV-2 is primarily extrapolated from SARS-CoV-1 and MERS as all three viruses cause severe respiratory disease in humans. But it is believed that with varied manifestations, not previously seen in SARS-CoV-1 and MERS, the SARS-CoV-2 is highly pathogenic, especially among the older age categories and people with comorbidities such as smoking, diabetes, cardiovascular ailments, and weaker immunity.

Biology of Coronaviruses
To put it into perspective, the World Health Organization warned in a statement released on May 11, 2020, that a review of studies by public health experts convened by the WHO last month found that smokers are "more likely to develop severe disease with COVID-19, compared to non-smokers." It is known that smoking affected by COVID-19," Direct deaths per year as a result of tobacco use are >7 million people.
Coronaviruses generally spread from human-to-human through respiratory droplets, and this spread is exacerbated by population density and poor hygiene. SARS-CoV-1 and SARS-CoV-2 enter the host cells by using spike protein on the surface of the viral capsid, which binds to angiotensin-converting enzyme II (ACE2) on type II alveolar cells leading to fusion of the viral and host cell membranes for the transfer of viral RNA into the host cytoplasm [4]. Once Strategies capable of disrupting S protein interaction with ACE2 are thought to carry significant therapeutic value. It is also because the binding affinity of SARS-CoV-2 S protein to ACE2 is 10-20-fold higher than for the S protein of SARS-CoV, and this particular aspect is attributed to higher infectious potential and contagiousness of SARS-CoV-2 as compared to SARS-CoV [4,5].

a. Intuitive use of angiotensin-converting enzyme inhibitors or ACE2 receptor blockers in SARS-CoV-2 infection
As the virus uses the ACE2 receptor to gain entry into the host cell, it is intuitive to use receptor blockers that can curtail viral entry. As per the WHO update on May 2020, there is a significant concern, based on considerations of biological plausibility and the observation on the overrepresentation of patients with hypertension and other cardiovascular comorbidities among patients with COVID-19 who have poor outcomes, that angiotensinconverting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) enhance susceptibility to coronavirus SARS CoV-2 raising the likelihood of severe COVID-19 illness [5][6][7].
There are pre-existing angiotensin receptor blockers (ARBs such as losartan, valsartan, and telmisartan) used in humans do present a novel therapeutic approach to block the attachment of SARS-

b. Chloroquine and Hydroxychloroquine: an anti-malarial drug repurposed
Also called 4-aminoquinoline is primarily an antimalarial drug. It is being repurposed to treat SARS-CoV-2 infection as mechanistically it can alter the glycosylation of ACE2, thereby decreasing the binding between the viral spike protein and the receptor ACE2 on the host cell, subsequently inhibiting viral entry into the host cell in vitro [13]. Moreover, hydroxychloroquine is also known to inhibit the Toll-like receptor (TLR) pathway, which is intrinsically involved in pro-inflammatory cytokine signaling [14], thereby reducing the inflammation. Reducing inflammation mainly in the lung, resulting from cytokine storm, has been thought to be a key aspect in controlling the disease.
Chloroquine inhibits SARS-CoV-2 infectivity [14], along with evidence showing that it also inhibits SARS-CoV-2 entry [15]. 500 mg Chloroquine twice a day for 10 days was prescribed in China SARS-CoV-2 infection, but further data on full efficacy are not available [16]. These beneficial effects of Chloroquine, which still needs proof in patients, come with toxicity previously described by many studies. These toxic effects ranging from dysrhythmias, hypotension, neurologic effects, oxidative stress, causing hemolysis, and potassium channel blockade have been seen at doses higher than 5 grams [17][18][19]. Hydroxychloroquine is less toxic than Chloroquine, but the exact mechanism remains poorly understood.
Its toxic effects, which overlap with Chloroquine, start at 4grams.
Overall, the data on the efficacy of hydroxychloroquine in treating COVID-19 is minimal, apart from anecdotal or sporadic success in treating SARS-CoV-2 infection [20]. Thus, caution is needed in using this drug, keeping in mind the com orbidities patients may have. SARS-CoV-2 has an affliction of comorbidities, as has been seen during the COVID-19 pandemic in China, Spain, Italy, Iran, and the USA (WHO update 2020).

Viral Replication Inhibitors
All RNA viruses depend on the host cellular machinery gilead.com/news-and-press/press-room/press-releases/2020/5/

gileads-investigational-antiviral-remdesivir-receives-us-food-
and-drug-administration-emergency-use-authorization-for-the-  In the absence of toxicity data on remdesivir, one can only extrapolate drug toxicity from the pre-existing nucleoside analogs used in the treatment of HIV. These nucleoside analogs cause metabolic acidosis, peripheral neuropathy, bone marrow suppression, pancreatitis, and myopathy, with each of these toxicities underpinned into mitochondrial dysfunction, as these analogs in addition to inhibiting viral polymerase, they also inhibit mitochondrial DNA polymerase-gamma, which, consequently, leads to decrease in mitochondrial DNA and proteins [24]. For Favipiravir, repeat-orally administered dose toxicity studies involving dogs, rats, and monkeys, showed adverse effects on hematopoietic tissues such as decreased red blood cell (RBC) production, and increases in liver function parameters such as aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin, and increased vacuolization in hepatocytes, in addition to testis toxicity (https://www.drugbank.ca/drugs/ DB12466).

Protease inhibitors
The protease has recently been defined [25], which closely resembles that of SARS-CoV-1 [25], and this may assist in further defining the specificity of either the existing protease inhibitors or designing new ones through SAR analysis.

Lopinavir/ritonavir (KaletraTM): Is combination drug treatment the future?
Lopinavir (ABT-378) has been used mainly for HIV, and it is a with patients showing a milder disease course with a considerable reduction in viral load and fever by day 21 [26]. Similar results in human trials against MERS were also observed [27].
In contrast, a recent randomized, controlled, and an openlabel trial with 199 hospitalized adult patients in Wuhan/China with certain SARS-CoV-2 infection and pneumonia, the oral administration of twice-daily 400 mg lopinavir and 100 mg ritonavir for 14 days showed that the treatment with lopinavir/ritonavir combination was not associated with a reduction of viral RNA loads or duration of viral RNA detectability as opposed to 100 controls [28]. These observations require further study, and clinical trials with lopinavir/ritonavir in COVID- 19 [34], and it appears that the combination therapy will be the future for yet another RNA virus, and this has already been seen in case of HIV where no single drug was fully effective.
In regards to toxicity, it is very well known for this class of inhibitors as they have been used in HIV treatment. So far, the experience with SARS-CoV-2 treatment does suggest toxicity with lopinavir-ritonavir, mainly at the level of nausea and vomiting, lipodystrophy, as seen before in HIV patients, and mild transaminase elevation across different studies, and the main reason for patient drop-out rates [35].

Conclusions
Past lessons with most of the drugs listed in this review we already have seen the emergence of drug resistance over time, attribute to viral mutations. In addition, resistance to vaccines has also been shown in seasonal influenza viruses due to less error correction activity of their nucleotide polymerases required in virus replication. In case of flu vaccines which are widely used seasonally and globally, the efficacy of flu vaccines against both influenza A

Conflicts of Interest
There are no conflicts to declare.