Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors (preprint)

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CL pro has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CL pro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CL pro . We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms (preprint)

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.

A large-scale COVID-19 Twitter chatter dataset for open scientific research -- an international collaboration (preprint)

As the COVID-19 pandemic continues its march around the world, an unprecedented amount of open data is being generated for genetics and epidemiological research. The unparalleled rate at which many research groups around the world are releasing data and publications on the ongoing pandemic is allowing other scientists to learn from local experiences and data generated in the front lines of the COVID-19 pandemic. However, there is a need to integrate additional data sources that map and measure the role of social dynamics of such a unique world-wide event into biomedical, biological, and epidemiological analyses. For this purpose, we present a large-scale curated dataset of over 152 million tweets, growing daily, related to COVID-19 chatter generated from January 1st to April 4th at the time of writing. This open dataset will allow researchers to conduct a number of research projects relating to the emotional and mental responses to social distancing measures, the identification of sources of misinformation, and the stratified measurement of sentiment towards the pandemic in near real time.

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy (preprint)

COVID-19 has globally spread and has become a new pandemic, but there are still no effective drugs or vaccines to treat or prevent this disease. SARS-CoV-2 invades human cells through its spike proteins interacting with human ACE2 receptors, which may cause severe respiratory syndrome. One strategy to prevent the virus from entering cells is the interruption of the viral spike protein interacting with human ACE2. Facing such an urgent situation, drug repurposing is a promising strategy for rapid drug development. Here, we selected approximately 15000 molecular candidates, including FDA-approved drugs from DrugBank and natural compounds from TCMSP, to perform virtual screening for potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human ACE2 receptor and viral spike protein. We found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin, which is extracted from indigo naturalis and polygoni tinctorii foliu, in TCMSP had the highest docking scores. Note that indigo naturalis and the other herbs we found have been applied to prevent infectious diseases in traditional Chinese medicine. We also found that raltegravir, an HIV integrase inhibitor, has a relatively high binding affinity. All the docking results are presented in this article. Based on these docking results, further work will continue to identify potential molecules to prevent the spike protein from binding with the ACE2 receptor.Authors Tianzi Wei and Hao Wang contributed equally to this work.