NWO-XL grant awarded to David Dulin by the Dutch Research Council (NWO)!!!

We have received new funding to explore the fundamental mechanisms of genome replication, transcription and packaging in coronavirus. This project brings together 8 PIs from Groningen, Delft, Utrecht and Amsterdam led by Dr. Dulin, and will receive ~3 M€ over the next five years. Congrats to all involved for putting together a very competitive proposal!

Announcement from NWO

Announcement from VU Amsterdam

“Quantitative parameters of bacterial RNA polymerase open-complex formation, stabilization and disruption on a consensus promoter” published in NAR!

Congrats to Subhas and Pim and all other authors, for putting together this fantastic work! They expanded our comprehension of the open complex formation in the bacterial RNA polymerase system using single molecule biophysics experiments and theoretical framework. Great collaboration with the Malinen (Turku, Finland) and Depken (TU Delft, Netherlands) labs. More to read here.

New NIH fundings to the Dulin lab for antiviral drug discovery!

The Dulin lab has been awarded funding from NIH to develop the next generation of antiviral drugs! We are part of two centers:

Rapidly Emerging Antiviral Drug Development Initiative – AViDD Center
Principal Investigator: Ralph Baric, Ph.D.
Institute: The University of North Carolina at Chapel Hill

Development of Outpatient Antiviral Cocktails against SARS-CoV-2 and other Potential Pandemic RNA Viruses
Principal Investigator: Jeffrey Glenn, M.D., Ph.D.
Institute: Stanford University School of Medicine, Stanford, California

We thank both Ralph Baric and Jeffrey Glenn for involving us in their very exciting and timely research program. We are looking forward to working with such talented group of scientists!

More information here.

Congrats Mona!

Mona Seifert – a former PhD student in the Dulin lab – graduated her PhD thesis on April 22nd. She was awarded the highest grade, Summa Cum Laude, meaning her PhD thesis is in the top 10% of all PhD thesis. We are all very proud of her, and wish her well for her future career. Bravo Dr. Seifert!

Mona with her examination committee, left to right: Vahid Sandoghdar, Ben Fabry, and (all to the right) Florian Marquardt.

New preprint on bacterial RNA polymerase open complex dynamics using magnetic tweezers!

Congrats to Subhas, Pim and colleagues to put this preprint together! We used magnetic tweezers to monitor the bacterial open complex formation, stabilization and disruption in different salt and temperature conditions. We discussed several kinetic models and reveal that the RNAP dissociates from the intermediate open state. Furthermore, we show the importance of using the “right” monovalent salt, i.e. potassium glutamate, to efficiently form a stable open complex. A great collaboration with Anssi Malinen lab in Turku!

Our article on the mechanism of action of antiviral nucleotide analogs against SARS-CoV-2 polymerase is now out in eLife!

Great news: our work on antiviral nucleotide analogs impacting the ability of the SARS-CoV-2 polymerase to elongate RNA is now out in eLife. Special congratulations to Mona and Subhas who have led the study! Thanks to the other lab members and and all the collaborators involved.

Bellow is the digest from eLife:

To multiply and spread from cell to cell, the virus responsible for COVID-19 (also known as SARS-CoV-2) must first replicate its genetic information. This process involves a ‘polymerase’ protein complex making a faithful copy by assembling a precise sequence of building blocks, or nucleotides.

The only drug approved against SARS-CoV-2 by the US Food and Drug Administration (FDA), remdesivir, consists of a nucleotide analog, a molecule whose structure is similar to the actual building blocks needed for replication. If the polymerase recognizes and integrates these analogs into the growing genetic sequence, the replication mechanism is disrupted, and the virus cannot multiply. Most approaches to study this process seem to indicate that remdesivir works by stopping the polymerase and terminating replication altogether. Yet, exactly how remdesivir and other analogs impair the synthesis of new copies of the virus remains uncertain.

To explore this question, Seifert, Bera et al. employed an approach called magnetic tweezers which uses a magnetic field to manipulate micro-particles with great precision. Unlike other methods, this technique allows analogs to be integrated under conditions similar to those found in cells, and to be examined at the level of a single molecule.

The results show that contrary to previous assumptions, remdesivir does not terminate replication; instead, it causes the polymerase to pause and backtrack (which may appear as termination in other techniques). The same approach was then applied to other nucleotide analogs, some of which were also found to target the SARS-CoV-2 polymerase. However, these analogs are incorporated differently to remdesivir and with less efficiency. They also obstruct the polymerase in distinct ways.

Taken together, the results by Seifert, Bera et al. suggest that magnetic tweezers can be a powerful approach to reveal how analogs interfere with replication. This information could be used to improve currently available analogs as well as develop new antiviral drugs that are more effective against SARS-CoV-2. This knowledge will be key at a time when treatments against COVID-19 are still lacking, and may be needed to protect against new variants and future outbreaks.

Welcome to our new members!

The Dulin lab wishes a very warm welcome to several new members! Sadegh Feiz comes from Iran and has joined our lab in Erlangen as a postdoc. Misha Klein is an former alumni of TU Delft where he did his PhD with our collaborator Martin Depken and joined us as postdoc in Amsterdam. Daniel Buc is master student at VU and will do his master project with us in Amsterdam. Welcome all and we wish you a great time and great science with us!