5000th protein structure at BESSY II – Starting point for a COVID drug
HZB team has identified 21 molecules as candidates for the development of antiviral drugs
Many proteins have a complex architecture that enables biological functions. Molecules can bind to specific sites on a protein and alter its function. A team at HZB has now investigated the Nsp1 protein, which plays a role in infection with the SARS-CoV-2 virus. They analysed protein crystals, previously mixed with molecules from a fragment library, and discovered a total of 21 candidates as starting points for drug development. At the same time, they also decoded the 5000th structure at BESSY II.
Even after the global pandemic caused by the SARS-CoV-2 virus has subsided, many variants are still circulating around the world, and the search for effective drugs continues. A team at HZB investigated the main domain of the so-called Nsp1 protein, which plays a role in SARS-CoV-2 infection. The Nsp1 protein blocks the production of the host cell's own proteins in the ribosomes of the host cells, thereby hindering the defence against the SARS-CoV-2 virus. Therefore, the main domain of Nsp1 is considered a promising target for the development of antiviral drugs.
The MX team at BESSY II conducted a high-throughput experiment with a fragment library. This fragment library consists of hundreds of small molecules, each of which was mixed individually with crystals of the Nsp1 protein. The crystals were then measured at the MX beamlines of BESSY II and their respective three-dimensional structures were determined. The results showed that 21 of these molecules were able to bind to the main domain of Nsp1. Many of these fragments, including the one shown in the 5000th structure, docked deep into a pocket of Nsp1 located near a functionally important region. ‘This makes it a promising starting point for the development of larger drug molecules that can disrupt Nsp1 during the replication of SARS-CoV-2,’ says Dr Frank Lennartz, first author of the study.
‘Fragment screening allows us to systematically test small chemical building blocks and determine which of them bind to specific sites on the protein. This reveals where the protein is vulnerable and at the same time provides starting blocks from which complex active substances can be developed,’ says Dr Manfred Weiss, head of Macromolecular Crystallography at HZB.
Publication:
Structural Biology (2025): Crystallographic fragment screening against SARS-CoV-2 nonstructural protein 1 using the F2X-Entry Screen and a newly developed fragment library
Frank Lennartz, Jan Wollenhaupt, Melanie Oelker, Paula Fröling, Uwe Mueller, Anke Deckers, Christoph Grathwol, Stefan Bräse, Nicole Jung and Manfred S. Weiss
DOI: 10.1107/S2059798325008563
Contact:
Helmholtz-Zentrum Berlin für Materialien und Energie
Research Group Macromolecular Crystallography
Frank Lennartz
(030) 8062-14629
frank.lennartz(at)helmholtz-berlin.de
Dr. Antonia Rötger
Press Officer
(030) 8062-43733
antonia.roetger(at)helmholtz-berlin.de
HZB press release, 26.02.2026