COVID-19 Evolution and Alternative Medicine-A Review

The current global health emergency, COVID-19, is not the first time that coronaviruses have posed a threat to human world shrinking our numbers by thousands. Before this SARS-CoV in 2003 and MERSCoV in 2013 have caused epidemics. Four months in existence, and it has already affected 1,995,983 people and taken over 131,037 lives worldwide, yet we do not have any specific treatment available with us and the management is purely empirical. Looking at the similarities between SARS-CoV and SARS-CoV-2 in origin, genomics, pathogenesis and epidemiology, we can bring the researches done for SARS-CoV in use which can be our guide in finding an effective management strategy against SARSCoV-2. There are various researches and studies reporting the use and effect of various phytochemical compounds in SARS-CoV treatment. Already, the thought has been put into action and in-silico screening for various natural plant compounds have been done to find a potential candidate compound. One such example is of curcumin, a secondary metabolite of turmeric, which is found to be effective against COVID-19 protease by molecular docking analysis.


INTRODUCTION
Coronaviruses are well known pathogenic organisms of humans and animals which cause a broad spectrum of respiratory, gastrointestinal, neurological and systemic diseases 1 .
Deriving its name from the word 'corona' 2 meaning outer fringe(because of the presence of spiky outer enveloped protein coat), coronaviruses belong to the family Coronaviridae which are further subdivided into four genera namely, Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus 3 .

Evolution of Covid-19
The genera Alphacoronaviruses and Betacoronaviruses contain viruses infecting both humans and animals (Table 1) 4,5 while the genus Gammacoronavirus and Deltacoronavirus contains viruses specifically infecting animals ( Table 2) 4 ; the first one being seen in whales and birds, and the latter ones are isolated from pigs and birds 4 .
Discovered in early 1930's as a pathogen causing mild respiratory infection in domesticated chickens 1 coronaviruses gained major attention in 2003 after the emergence of SARS(Severe Acute Respiratory Virus) which caused a major global epidemic wiping out thousands of global population.
Before 2003 epidemic was inked in the history of humankind, coronaviruses were known to cause mild respiratory infections. It was the first time, when coronaviruses were seen posing such a serious threat. This was a game-changing event which led to various researches. As reported, SARS was known to be caused by cross species transmission-from bats to humans.
Since then, coronaviruses are seemingly undergoing variety of mutations and leaping into humans causing infections, both mild and severe. After SARS, four more strains of coronaviruses have been recognised till now of which two strains namely, HCoV HKU-1 and NL63 are known to cause mild respiratory disease while two strains namely, MERS-CoV and SARS-CoV-2 have caused epidemics affecting human population in large numbers and  The latest recently recognised strain of all, SARS-CoV-2, was recognised in December 2019, in Wuhan city of China. Seeing its genomic similarity with SARS-CoV, it is thought to have paved its way to humans from animals through the live animal markets of China. The two probable theories of the origin of the virus gives bats [11][12][13] or pangolins 13, 4 as the natural host of the virus, bats being the most closest. The virus, likely, then mutated and evolved to spread most probably though an intermediate animal bridge to humans and now human to human transmission can be easily noted.
Being of the common origin as of SARS-CoV, it was hypothesized that the virulence of SARS-CoV-2 will also be affected by the increasing temperatures especially above 39°C (same as in case of SARS-CoV). According to the various studies conducted in this regard, the result remains inconclusive. According to a study conducted in China, COVID-19 mortality decreased with increase in ambient temperature (above 39°C) along with increased absolute humidity 15 . A study conducted by Wang et al. 16 showed reduction in transmission of the disease while studies conducted by Ye Tao et al. 17 and Zhu et al. 18 showed ambient temperature had no effect on the transmission of SARS-CoV-2.

Complementary Medicine
Since the emergence of human race, plants have been the source of countless compounds having medicinal properties and lead to drug discovery. Since the ancient times, Indian Ayurveda, Traditional Chinese Medicine Literature, ancient Egyptian Ebers Papyrus all gives description of various plants and herbs having medicinal properties which are even today used all over the world for various health benefits. Different plant compounds act as immune boosters and can act as antibacterials, antivirals as well as antifungals. The coronaviruses encodes various proteins which enables its functioning. Many plants produce compounds interfere with these proteins and can become a target for drug development. Since the gene sequence of COVID-19 has very high similarities between the man proteins of COVID-19 and in SARS or MERS, thus previously reported anti-SARS or anti-MERS natural compounds may become a valuable guide to find the affective anti-COVID-19 herbal plants (Table 3).
There are more than a dozen of proteins which are encoded by coronavirus. Some of these proteins are essential to viral entry and replication. Papain-like protease (PLpro), 3C-like protease (3CLpro) and spike protein are the well studied proteins so far. All of these three proteins make attractive targets for drug development. Some of the herbal plants have been screened in silico by Narges & Neda 2020 to find the inhibitors for COVID-19 proteases, which could be an effective strategy for combating against this deadly virus. Due to the strong interaction of these natural compounds with enzymatically conserved regions and specific functionality, these compounds can be considered as effective antiviral drugs due to their natural origin and less likely to produce  HCoV-OC43 triggered apoptosis adverse effects if they enhance the interaction. Out of the eight tested secondary compounds curcumin was found to have strong interaction with protease of COVID-19 19 . In another studies in silico screening with AI has been performed. It is a very fast method of screening reducing the cost of experiment as well as few human trials are required which leads to a fast development of drug 20 . Until now, many existing allopathic drugs are also being tried continuously which may prevent worsening of the clinical condition of the patient and provide them early relief. Some of them being given to the patients include remdesivir, lopinavir, chloroquine or hydroxychloroquine and interferon beta-1a. Recently, convalescent plasma therapy is being tried 21 . But all these medicines have many potentially serious side effects thus limiting their use to critical patients only. Moreover, the efficacy of these medicines has not yet been proven and thus are restricted to compassionate use only 22 (Table 4).
R a n d o m i s e d C o nt ro l Tr i a l s a re continuously being done to see and prove the efficacy of these drugs and to find an appropriate effective treatment. One of the biggest international clinical trials is being conducted by WHO which has been given the name "Solidarity". Seeing the urgency of the need of an effective treatment against the COVID-19, this trial is said to reduce the normal time taken by 80%. Four regimens are currently included namely, remdesivir, lopinavir with ritonavir, chloroquine or hydroxychloroquine and lopinavir with ritonavir with interferon beta-1a 23 .
Although same is the case with complementary medicine and their use is dependent upon their recorded effects in the

CONCLUSION
Although modern medicine came over traditional medicine in Darwinian process especially in developed countries, it is still being used widely by much of the population especially in developing countries. In fact, the trend is continuously growing towards the use of traditional medicine which is now no longer "the poor man's alternative to conventional care" 26 . Although the ancient traditional medicine seriously lacks validation and standardization 27 , but the increasing tilt of the society towards the alternative medicine source due to widespread increasing rate of chronic diseases as well as lack of modern allopathic medicine in treating various infectious diseases due to antimicrobial resistance, has lead to various researches and studies which proves their efficacy and safety in various advanced clinical trials. Lately, when the world is under attack by COVID-19 and where modern medicine is incapable of saving us our heads turn towards the traditional medicinal source to be our shield. A lot of researches are being done to find the potential candidates from the conventional herbal pool which can prevent the spread and stop the effect of the virus.
In view of such newly emerging and reemerging infectious diseases such as Ebola virus, Nipah virus, Zika virus, COVID-19, having potential to cause epidemics and thus seriously affect the human race not only in severity but also in numbers, traditional medicine can lend us a way out which, as quoted by WHO, is the care that is close to homes, generally available, accessible, affordable and sometimes the only care available to people at primary health care level 26 .