Get a bird's eye view of the pandemic that has engulfed the world.
COVID-19, the disease caused by the notorious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has wreaked havoc in human lives globally threatening their very existence and pushing humans back into their homes. The world is faced with grave issues such as staggering mortalities, debilitating morbidities, lost livelihoods, weakening economies to name just a few, and to think that all this has been caused by an entity that the most superior race on earth hasn’t yet successfully categorized into living or non-living! Global research focused on cornering this culprit and overcoming this debilitating situation is progressing at an unimaginable rate resulting in immense amount of information and data being put out there. A review that puts all this information into a contextual perspective is the need of the hour to ensure availability of comprehensive information.
SARS-CoV-2 is a beta coronavirus comprising of four proteins, S (spike), E (envelope), M (membrane) and N (nucleocapsid) that are responsible for its structural and functional integrity, besides the nucleic acid (RNA), which is the core of its existence. The pathology of the virus begins with the spike protein attaching onto the membrane of a host (human) cell exhibiting the angiotensin converting enzyme 2 (ACE2) receptor to enter the cell. The ACE2 receptor, so crucial to the process of infection, is expressed on many human cells predominantly the lung alveolar cells, thereby explaining the affinity of the virus to the lungs and the manifestation of pathologies related to the lower respiratory tract. Once the virus has successfully attached to the host cell, its entry into the cell is facilitated by mechanisms driven by the host cell itself! Certain human enzymes such as proteases capable of digesting proteins cleave the fusion-mediating subunit of the S protein called S2 triggering a conformational change that facilitates the fusion between the viral envelope and the host cell. The ease of the plasma membrane fusion pathway compared to the endosomal membrane fusion pathway is what makes it more efficient and sought after by most viruses owing to the facilitative role played by host components. The immune system generates an array of antibodies targeted at preventing the attachment of the virus to the host cells by blocking receptor access or by binding to the receptor-binding motifs (RBMs) present in the S protein. However, the virus sometimes successfully evades most of these immune mechanisms to cause disease in the host. Therefore, a lot of antiviral compounds being researched are those that inhibit the host proteases thus suppressing the membrane fusion process and preventing viral entry into the cell. Such therapeutic agents can prevent the virus from affecting the host system despite the successful initiation of the infection process. While a specific antiviral for SARS-CoV-2 is still being researched upon, a more general approach involving broad-spectrum antivirals such as lopinavir/ritonavir (anti-HIV), remdesvir (anti-ebola), neuraminidase inhibitors (anti-influenza), peptide EK1(anti-coronavirus), arbidol (blocks viral fusion) among others are being used for clinical treatment of COVID-19. A study by Jin et al (Structure of Mpro from COVID-19 virus and discovery of its inhibitors, 2020) targeting Mpro, the key SARS-CoV-2 enzyme mediating viral replication and transcription has indicated the potency of Ebselen, a molecule that interacts non-covalently with Mpro restricting its activity. While some of the molecules studied have been FDA approved, some remain under clinical trials. Some research groups have also claimed the effectiveness of nanomaterials as antivirals that can lower the infectivity rate up to 96.5 to 99.9%. Hydroxychloroquine and choloroquine, two drug molecules known for their anti-malarial activity have demonstrated antiviral activity in vitro and are known to be effective in preventing viral entry into the host cell. Chemoprophylaxis involving these two drugs although debatable for their side-effects has been approved by the FDA and is being adapted by a lot of countries as a desperate measure for critically ill patients. TMPRSS2, a human protease critical for cellular infection by SARS-CoV-2 with known and available inhibitors has no known indispensable physiological functions and has therefore been explored as a potential target for combating COVID-19 by Konrad et al (TRPMSS2 and COVID-19: Serendipity or opportunity for intervention? 2020).
The phylogenetic analysis of the SARS-CoV-2 virus has shown a 96% sequence identity to the RNA from the bat coronavirus lending a bad name to bats in association with the etiology of the disease. Pangolins have also been identified as a probable intermediate host based on phylogeny. Researchers from countries all over the world are therefore attempting to grow the virus in bat cell lines to enable studies focused on understanding the pathogenesis and replication strategy of SARS-CoV-2.
The devastating effect of the virus on hosts with co-morbidities such as hypertension, diabetes, cardiac conditions or in the geriatric population is staggering. Hypertension is especially challenging since the major antihypertensive drugs used are ACE2 inhibitors and angiotensin receptor blockers (ARBs). ACE2 is a common interface between being a counter-regulator of the renin-angiotensin-aldosterone-system (RAAS) and a receptor for SARS-CoV-2. ACE2 expression in cells infected with SARS-CoV-2 has been found to be downregulated preventing its protective effect in organs, which is probably responsible for organ injury seen in COVID-19 (Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics, 2020; Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury, 2020). This also suggests that the virus proliferates when the ACE2 expression is inhibited thereby indicating that the antihypertensive drugs may be a risk factor for hypertensive patients.
Global research oriented towards the development and production of vaccines effective in preventing COVID-19 are being largely focused upon to prevent the staggering effects of the disease. An evidence of the commendable effort is seen in the number of vaccine candidates that are already in clinical trials within such a short span of time. Alternate therapies such as plasma therapy which uses the plasma from the blood of recovered COVID-19 patients (convalescent plasma) containing antiviral antibodies for the treatment of critically ill COVID-19 patients are also being adapted by the medical fraternity and have so far shown some promising results.
The accelerated pace at which research for the development of prophylactic and therapeutic options against COVID-19 is advancing holds the promise to strategize means to defeat this disease in near future.
コメント