Coronaviruses (CoVs) are the etiological agents of either common colds and severe diseases such as the 2002 Severe Acute Respiratory Syndrome (SARS-CoV-1) and the 2012 Middle East Respiratory Syndrome (MERS-CoV). In 2019 the viral strain SARS-CoV-2 previously not detected in humans was identified in China as responsible for the current global outbreak.
All these epidemics are commonly associated with the elevated genetic mutation rates, which translate into a high probability to infect hosts, including humans (i.e., zoonosis). No specific drugs are yet available to effectively treat COrona VIrus Diseases (COVID-19) as many associated morbidities and deaths are constantly recorded.
Currently, media brainstorm on the use of vaccines shadows and drains out important resources, which are vital to foster the progress (although discrete) in developing adequate drugs to tackle SARS-CoV-2 spreading and its associated diseases. At present, the only effective measures still are precautional and all aimed to avoid any viral transmission among individuals. However, the containment measures adopted have a dramatic impact on the economy and social life. Therefore, the identification of drugs that can impair viral replication and effective in the ongoing pandemic are in high demand.
This project aims to identify new and effective inhibitors of the main protease (Mpro) and papain-like protease (PLP) of SARS-CoV-2, as well as SARS-CoV-1 and MERS, by mean of a skillful and complementary combination of computational and experimental approaches. Specifically, the target-based in silico screening will use multiple Mpro and PLP crystallographic structures available as templates. Inhibition of Mpros and PLPs by most promising virtual hits will be assessed using lab bench biochemical assays and then further investigated for their antiviral activity through in vitro cellular and in vivo experiments.
the current proposal efficiently and rapidly will tackle the currently alarming sanitary circumstances caused by the SARS-CoV-2 outbreak, which assumed within a short time frame global dimensions and resulted in severe and not previously reported impairments to all sectors of human life in the modern era. The overall scientific scope is to identify highly effective and specific inhibitors of the viral Mpro and PLP, which are among the most promising and well-characterized drug targets among CoV strains. These enzymes are essential for i) processing the polyproteins translated from the viral RNA and ii) ensuring viral genome replication. The managerial structure and scientific orientation of this proposal are deeply committed to address the main challenge ¿to reduce the time to reach clinical proof of concept in medicine development¿ by concentrating high qualifications and experiences of the units within the field of molecular biology, in silico target drug discovery, drug design and development applied to antivirals against highly relevant druggable targets.
the proposal aims to advance R&D based antiviral research by developing an integrated and reliable approach, identifying new therapeutics for CoV related diseases, and filling a gap that is still unsolved. In this scenario, the proposal will immediately focus on the computational and experimental search of inhibitors of the Mpro and PLP of CoV strains of interests.
Thanks to the availability of Mpro and PLP structures, recently solved in complex with small molecule inhibitors, target-based approaches will be used, including pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations. These are fast, highly reliable, and cost-effective methods to quickly prioritize highly promising compounds among screening libraries.
the proposal aims to provide highly potent and specific drug candidates targeting Mpro and PLP of SARS-CoV-1, SARS-CoV-2, and MERS-CoV to prepare for possible future outbreaks. As already outlined, most of the issues related to the current pandemic outbreak of COVID-19 are due to the lack of specific and available drugs to counteract the spread of SARS-CoV-2. Thus, it is of utmost importance to develop drugs that will constitute the arsenal of therapeutics also for further outbreaks.