Uncovering the human proteins targeted by COVID-19

New research published by the University of California has revealed over 230 interactions that COVID-19 proteins establish with human proteins. This work offers insights into how COVID-19 infection occurs and identifies almost 70 potential drug-targets.

Coronavirus Disease-2019 (COVID-19) has infected over 1,030,000 people in more than 100 countries (data 03/04/2020), but due to a lack of known molecular detail, there are no current antiviral compounds available to combat the virus. Interactions between host cell proteins and viral proteins are at the forefront of infection, where viruses such as COVID-19 hijack host resources to propagate. There is an ever-developing arms race between host antiviral factors, which aim to hinder infection, and viral antagonistic factors, which aim to counteract host defences. Revealing this complex network of interactions can help us understand how viral infection occurs and can reveal therapeutic targets to combat infection.

The Krogan labrevealed the interactions of 26 of the 29 COVID-19 proteins in human cells using a technique known as affinity purification followed by mass spectroscopy (AP-MS, Figure A), which allowed them to probe protein-protein complexes with high sensitivity. The researchers identified over 230 human interactors which participate in a wide array of key cellular pathways such as innate immunity and the protein unfolded response (Figure B). Using bioinformatic analysis, they reveal almost 70 compounds which target key parts of the network and may represent potential antiviral drugs. Current tests for antiviral activity are ongoing. The work also reveals many common interaction partners between COVID-19 and other viruses also associated with pulmonary conditions such as West Nile Virus and Mycobacterium tuberculosis, suggesting that they may have similar mechanisms of infection.

This work contributes significantly to our current understanding of COVID-19 and furthers our efforts to find compounds which may combat infection. 

Written by Catherine Truman, DTP DPhil student

Original publication:

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing. David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, Jiewei Xu, Kirsten Obernier, Matthew J. O’Meara, […], Pedro Beltrao, Kevan Shokat, Brian K. Shoichet, Nevan J. Krogan,. BioRxiv. DOI: https://doi.org/10.1101/2020.03.22.002386

Oxford Vaccine Effort Towards COVID-19

Oxford University has joined the global effort to fight COVID-19 (also referred to as SARS-Cov2) and is recruiting healthy volunteers to test a new vaccine. This comes after both the USA and China announced that they were starting clinical trials of COVID-19 vaccines. The team from the University’s Jenner Institute is working in collaboration with the Oxford Vaccine Group to conduct the trial which has been approved by UK regulators.

The team, led by Prof. Sarah Gilbert, Prof. Andrew Pollard, Prof. Teresa Lambe, Dr. Sandy Douglas and Prof. Adrian Hill, started designing the vaccine on the 10th of January as soon as the first genome sequence of COVID-19 was made publicly available. The vaccine candidate put forward for the trial uses a chimpanzee adenovirus vector (ChAdOx1) previously developed by the Jenner Institute. It was chosen as the most suitable vaccine technology as only one dose is required to generate a strong immune response and the adenovirus vector is defective so cannot cause an infection in the vaccinated individual. So far, the ChAdOx1 vector technology has been successfully used in vaccines targeting over 10 different diseases.

Coronaviruses (including COVID-19. SARS and MERS) have a club-shaped protein on their surfaces called spike protein. Previous studies of coronavirus vaccines suggested that the spike protein is a good vaccine target. The genetic sequence of the COVID-19 surface spike protein is introduced inside the ChAdOx1 vector. Once the ChAdOx1 vector enters a cell, the host machinery transcribes and translates the genetic sequence and the COVID-19 spike protein is expressed. The spike protein then serves as a training tool for B cells, leading to the production of antibodies against the spike protein. Antibodies work as tailored weapons targeting a specific pathogen, in this case, COVID-19. A vaccinated individual is expected to develop an effective immunological arsenal against COVID-19 which will be instrumental to fight and prevent the infection or, at least, reduce its severity.

Due to the urgent need for means to fight the COVID-19 pandemic, the production of the vaccine is already being scaled up to produce enough stock for large clinical trials and potentially future deployment. This will ensure that as soon as the vaccine is proven safe and effective, it can be available for the people that need it the most, including frontline healthcare workers, the elderly and those with underlying health conditions.

Writen by Kate Dicker, WT IITM DPhil student

References:

  1. Clinical Trials Arena. Covid-19: China to launch clinical trials for coronavirus vaccine, (2020).
  2. Clinical Trials Arena. First US clinical trial of Covid-19 vaccine candidate begins, (2020).
  3. University of Oxford. Oxford COVID-19 vaccine programme opens for clinical trial recruitment, (2020).
  4. University of Oxford. About the COVID-19 vaccine trials ,(2020).

Positions available in the Gallego lab

Our colleagues from the Gallego lab in Barcelona, are now recruiting a Postdoc and a PhD position.

Oriol Gallego works at the interface between Cell Biology and Structural Biology, and aims to resolve biological mechanisms driving cell growth. His group develop new intracellular nanotools that help to enhance the resolutive power of live-cell imaging. This toolbox allows to answer biological questions that could not be tackled by other means. They have a brand new lab and equipment. The Gallego lab is based PRBB, an excellent research center in Barcelona, which is equipped with state-of-the-art facilities and with a highly international scientific environment. 
They seek for a Postdoc with expertise in quantitative live-cell microscopy (ideally, a microscopist with background in biophysics, optical physics or image analysis) and a PhD student (background in life-sciences, ideally with expertise in biophysics, biochemistry, structural biology or bioinformatics) to join our lab. Please, see the links for more details on the Postdoc and the PhD positions and visit www.gallegolab.org.

iCASE scholarship (PhD/DPhil) to elucidate how the brain develops

This scholarship will allow you to work in a multidisciplinary team between Prof. Ilan Davis (Microscopy and brain development), Alfredo Castello (RNA biology and viruses) and Martin Booth (Industrial partner Aurox.ltd).

Combining these expertise, we will build an affordable very fast confocal microscope with a small footprint, dedicated to prolonged live cell imaging of explanted brains in 3D, as well as to rapid 3D imaging of multiple single RNA molecules. Once built the microscope will have many applications. Depending on the background of the student, the work will involve a balance of optical engineering / biological experiments / data analysis. The student will have access to world leading training and collaborations through Micron Oxford to all the relevant expertise required for these three disciplines.