Publications
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Abstract
Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The RBD domain of SARS-CoV-2 Spike protein is a promising drug target due to its pivotal role in viral-host attachment. These specific structural domains can be targeted with small molecules or drug to disrupt the viral attachment to the host proteins. In this study, FDA approved Drugbank database were screened using a virtual screening approach and computational chemistry methods. Five drugs were short listed for further profiling based on docking score and binding energies. Further these selected drugs were tested for their in vitro biological activity. There was significant correlation between the prediction from computational studies and the actual RBD-ACE2 binding inhibition by the drugs. Then, we performed a series of studies that mimic some of the biological events seen in COVID-19 patients such as secretion of IL1β, presentation of a more thrombogenic endothelium by production of thrombomodulin and accumulation of inflammatory cells such as monocytes in the lungs. Of all the drugs, most promising drug was Ertugliflozin which is used for type-2 diabetes. This drug possesses several desired properties and may be a good candidate for immediate repurposing for treatment of COVID-19.
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The world is suffering from a pandemic currently, the likes of which have not been seen in recent history. The virus causing this pandemic is called novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, 2019-nCoV) and the disease caused by it is called COVID-19. It is believed to have initiated in Wuhan, China and rapidly spread from there to other parts of the world thru individuals traveling. COVID-19 has been impacting a large number of people worldwide, being reported in most countries with fatalities in millions globally.
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Abstract
COVID-19 pandemic has ravaged the world and vaccines have been rapidly developed as preventive measures. But there is no target-based therapy which can be used if infection sets in. Remdesiver and dexamethasone were not designed to combat COVID-19 but are used clinically till better targeted therapies are available. Given this situation target based therapies that intervene in the disease pathway are urgently needed.
Since COVID-19 genesis is driven by uncontrolled inflammation/thrombosis and protein kinases are critical in mounting this response, we explored if available tyrosine kinase inhibitors (TKI’s) can be used as intervention. We profiled four TKI’s namely; Lapatinib, Dasatinib, Pazopanib and Sitravatinib which inhibit tyrosine kinases but are completely distinct in their chemical structures.
We demonstrate using in silico and an in vitro 3D-human vascular lung model which profiles anti-inflammatory and anti-thrombogenic properties that all four TKI’s are active in varying degrees. Our findings that chemically different TKI’s which share kinase inhibition as the common mechanism of action are active, strongly indicates that it’s a tyrosine kinase target-based activity and not off-target arbitrary effect. We propose that TKI’s, approved for human use and widely available, can be rapidly deployed as specific target-based therapy for COVID-19.
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Abstract
COVID19 continues to be a serious threat to human health and mortality. There is dire need for new solutions to combat this pandemic especially for those individuals who are not vaccinated or unable to be vaccinated and continue to be exposed to the SARSCoV2. In addition, the emergence of new more transmissible variants such as delta pose additional threat from this virus.
To explore another solution for prevention and treatment of COVID 19, we have produced chicken egg derived IgY antibodies against the Receptor binding domain (RBD) of SARSCoV2 spike protein which is involved in binding to human cell ACE2 receptors. The – RBD IgY effectively neutralize the binding of RBD to ACE2 and prevent pseudovirus entry in a PRNT assay. Importantly our anti-RBD IgY also neutralize the binding of Sars CoV2 delta variant RBD to ACE2. Given that chicken egg derived IgY are safe and permissible for human consumption, we plan to develop these ingestible antibodies for prevention of viral entry in the oropharyngeal and digestive tract in humans as passive immunotherapy.
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Abstract
Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.
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Abstract
There has been intense interest in Hydroxychloroquine (HCQ) since it is being prescribed off-label for many SARS-CoV-2 infected patients. Despite, several clinical studies with mixed results, many physicians prescribe HCQ claiming that it reduces the incidence of mortality due to COVID-19 disease, when given early enough. Randomized clinical trials, however, indicate that this drug may be marginally effective for COVID-19 patients.
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Abstract
Discovery of new drugs is an expensive and time-consuming process. Average time taken from bench to bedside (idea to drug launch) is about 12 years including clinical trials. The emergence of COVID-19 pandemic has demonstrated that there is a dire need to be able to launch therapeutics much sooner than the traditional timelines. As such the industry is reinventing the process to deliver drugs much faster.
As such we present here a new paradigm of identifying drugs for COVID-19. It uses three fundamental principles, viz.,
1) using existing FDA approved drugs which have been approved for other diseases, so their safety is proven,
2) Using computational rational approaches for choosing the best drugs against the target of interest such as the receptor Binding Domain of the Spike Protein of COVID-19, and, finally, 3) validation of these short-listed drugs through in vitro disease models. We estimate that such an approach could crash the timelines of bench to bedside to 5 years or less, thus fulfilling the needs of urgent unmet diseases such as COVID-19 faster.
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Abstract
SarsCoV2 virus driven pandemic continues to surge propelled by new mutations such as seen in Omicron strain. Omicron is now rapidly becoming the dominant strain globally with more than 30 mutations in the spike protein. The mutations have resulted in Omicron strain escaping most of the neutralizing antibodies generated by the current set of approved vaccines and diluting the protection offered by the vaccines and therapeutic monoclonal antibodies.
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Abstract
Omicron strain is the latest variant of concern of SarsCov2 virus. The mutations in this strain in the S protein Receptor Binding domain (RBD) enable it to be more transmissible as well as escape neutralizing activity by antibodies in response to vaccine. Thus, Omicron specific strategies are need to counter infection by this strain. We investigated a collection of approved drugs shown to antagonize the binding of native strain RBD to human ACE2, for their ability to antagonize binding to Omicron strain RBD.