Structure based development of new agents against Covid-19

Antiviral therapies are often most effective when administered in combination. Most of the global academic and industrial pharmaceutical research in Covid-19 is currently directed toward developing a vaccine or probing existing drugs for efficacy against SARS-CoV-2. Efforts to develop a new antiviral agent have been of lower priority because of the relatively long development cycle. In collaboration with expert virologists at the Chinese Academy of Medical Sciences, we want to address this deficit by developing small molecule antivirals using advanced crystallography.

We will elucidate the molecular structure of various coronavirus proteins using methods of X-ray crystallography. In parallel, we will develop biophysical tests to assess the transferability of established antivirals as potential Covid-19 therapeutics. The knowledge gained from these two approaches will then be combined in a third step to develop novel Covid-19 antivirals or to augment the efficacy of established antivirals.

We aim to provide a window into the molecular structure of coronavirus proteins and the structural basis for its potential interactions with antivirals. This structural insight may serve as the basis for current and future drug discovery efforts against SARS-CoV-2 with the potential to be utilized against related, prospective coronaviruses. We will explore the structural dynamics of the coronavirus proteins by monitoring potential changes in structure as a function of temperature. This is a technique that can reveal intricate molecular interactions and help guide the design of antivirals. The pipeline we establish here may also serve as a framework to target other disease relevant protein targets.

The purpose of this project is to support the global research effort against SARS-CoV-2 by providing new insights into the interaction of small molecule antivirals with different coronavirus proteins at the atomic level, facilitating antiviral development. The state-of-the-art infrastructure at the synchrotron Swiss Light Source (SLS) at the Paul Scherrer Institute is ideally suited to pursue this strategy, and through our academic setting we are afforded the flexibility and adaptability to provide pharmaceutical companies and academic groups in Switzerland with the necessary information to synthesize, test, and deliver new antivirals.

Implementing a crystallographic fragment screening pipeline to advance preclinical drug discovery efforts toward the development of COVID-19 antivirals