Page 13 - Periodic ISSUE 8

results, novel protease inhibitors were designed and
synthesized by Lennart Brewitz; some of these show
encouraging protease inhibition activities.

Along with in-house screening of drugs, this assay has
also been used in collaboration with PostEra Inc. and
a multidisciplinary cohort of scientists from academia
and industry to screen compounds from the COVID
Moonshot Project: a crowdsourced and collaborative
initiative that aims to speed up discovery of the
COVID-19 antiviral compound. Florian Modicom, Sourabh Mishra and Conor Dean – members of
the Fletcher group working on COVID-19 research – relax outside
Drugs and treatments the lab.
The Schofield group has also been part of a highly
Image: © Filip, Adobe Image Library. collaborative investigation into repurposing the existing administered intravenously and was previously tested
respiratory drug almitrine to treat COVID-19 patients. as a treatment for hepatitis C and the Ebola virus. This
Many coronavirus patients die on ventilators because new research will use rhodium-catalyzed reactions,
their lungs cannot take in enough oxygen. Almitrine, developed in the Fletcher lab, to make a variety of
C
previously used to treat chronic obstructive pulmonary
candidate molecules that look similar to Remdesivir.
oronavirus Research disease (COPD), is a respiratory stimulant that helps These will then be assessed based on their biological
increase uptake of oxygen into blood in the lungs.
activity, with the ultimate aim being effective inhibition
A collaboration across departments of the university, of COVID-19 viral replication.
The Department of Chemistry has been playing its part in the fight against COVID-19. led by Peter Robbins from the Department of References: Goetzke, F. W. et al., Angew. Chem. Int. Ed. 58
Thomas Player explains some of the most recent research. Physiology, Anatomy and Genetics, aims to determine (2019) 12128–12132 (doi.org/10.1002/anie.201906478),
if almitirine will have a similar effect in COVID-19 Schäfer, P. et al., Nat. Commun. 8 (2017) 15762 (doi.
org/10.1038/ncomms15762).
patients and prevent them being put on ventilators. The
Funding new research peptide substrates were Schofield group, and in particular Tharindi Panduwawala Analysis and screening
Chris Schofield was part of the committee responsible synthesized to monitor and Alistair Farley, have developed routes to synthesise Potential methods for inhibiting the virus responsible
for distributing the University’s COVID-19 Research the activity of M . and analyse almitrine, and the drug will now be tested for COVID-19 are being investigated using mass
pro
Response Fund, which has received very substantial Tobias John, a DPhil in clinical trials funded by LifeArc at three UK hospitals. spectrometry in native conditions in a collaboration
philanthropic donations during the crisis. It has funded student in Schofield Since almitrine is a relatively cheap drug it could be between Carol Robinson, Chris Schofield, and
projects related to COVID-19 across the University, group, spent many particularly useful where ventilators are not readily colleagues in the Department of Biochemistry. They
including four in the Department of Chemistry. available, improving patients’ lung function before the
days synthesizing disease progresses too far. have been considering the effect of small molecules
Inhibiting the virus and purifying natural that can bind to the virus far from its active site.
One project in the Schofield group saw DPhil student peptide substrates of “We hope that this massive and very productive set of Drugs that bind non-covalently in this way can limit
Tika Malla and postdoctoral researcher Tony Tumber viral enzymes. This key national and international collaborations on COVID-19 its activity, and may also be more stable and have less
developing a mass spectrometry based assay to screen work was carried out Tika Malla, member of the Schofield will be maintained over the longer term,” said Professor toxic effects than other drugs that bind irreversibly.
many different compounds and assess how they may during the peak of the group, next to a RapidFire mass Schofield, “to address not only potential future Using mass spectrometry they characterised a section
Pro
inhibit viral enzyme targets, as prepared by Martin lockdown period this spectrometry sampler and injecting pandemics but also viral diseases in general, particularly of the SARS-CoV-2 protein M – the main protein
a sample from a 96-well plate. This
Walsh and his team at the Diamond Light Source. The spring, with many late equipment was crucial for the screening in middle and lower income countries where diseases responsible for processing mature SARS-CoV-2 – and
aim of this project is to identify existing drugs that may nights but always with assay developed by the Schofield group. like dengue and Zika fever are major killers. There is found that several small molecules can bind non-
be effective against the virus, as well as developing new stringent consideration just a chance that these efforts will change the way covalently to this protein and slow its activity. This
treatments. of health and safety and increased hygiene practices. the world works for the better in terms of infectious is a promising and straightforward route to test and
The work was fantastically well supported by the CRL diseases.” optimise potential antiviral drugs.
The assay was designed to monitor the inhibition of the staff including stores members, Adam Hardy, and the
main protease (M ). Unlike human proteins, the viral wonderful cleaners. Stephen Fletcher’s research group has received a Biophysics of COVID “spike” protein
pro
proteins are synthesised in long polypeptide chains. The grant from UK Research and Innovation in order to The university’s COVID-19 response fund has also
function of M is to cleave these polypeptide chains Unsure how the disease would progress, members of develop COVID-19 specific viral RNA polymerase awarded funding to Philipp Kukura’s research group
pro
and release the proteins to carry out their downstream the Schofield group were able to optimise a method for inhibitors. This is a type of drug that prevents in order to investigate the molecular biophysics of the
roles either individually or by forming a complex with comparing how effective many different compounds replication of the virus’ genetic material. Their work protein responsible for COVID-19. In particular, they
other proteins. As the polypeptides are up to 20 are at impairing the coronavirus protein – a vital tool is inspired by Remdesivir, an antiviral drug that is will be using their state-of-the-art mass photometry
kilodaltons long and synthetically less feasible, short for assessing the efficacy of new drugs. Based on these

12 13
Periodic The Magazine of the Department of Chemistry The Magazine of the Department of Chemistry Periodic