Research contribution on COVID-19

A lot of information has been shared in recent times about viruses and how they can be combatted. In this section, we aim to give you a greater understanding of the background behind Diamond’s work on viruses and hopefully explain some terms you may not have been previously familiar with. 

Structural biology enables scientists to look in detail at the structure and function of macromolecules, such as proteins and nucleic acids. To do so requires very powerful analytical tools to capture high-resolution data and uncover details so that this information can be used to aid in the development of pharmaceutical drugs.

Structural biology is now in the front line of responses to emerging viral diseases. This was first demonstrated in the development of drugs against HIV. In the years after AIDS was identified in the early 1980’s, hundreds of structures were solved for several key viral enzymes with potential drug candidates, leading to the development of potent new compounds which are now part of effective therapy, for example structural biology played a key role in the first clinically approved HIV protease inhibitor developed by Roche Saquinavir in 1995. A key lesson was that even rapidly evolving RNA viruses can be checked by highly active multi-drug therapy.

Like many things in life, if you don’t know how something works you can't work out how to change it, or in the case of a virus, stop it from working. To find a vaccine or cure for a virus it is imperative to have as detailed a knowledge as possible of how it works at a molecular level. We already know that the virus (SARS-CoV-2), like many viruses, is spherical like a football. The only difference is that you can hold a billion virus molecules on a pinhead! Together with its spherical shape, the virus has ‘spikes’ all around it. These ‘spikes’ are glycoproteins, which play a key part in the way the virus attacks cells in the body. The virus also contains a single strand of RNA, a long molecule that is responsible for the replication of the virus and therefore its infectious nature.

RNA (ribonucleic acid) is a nucleic acid that is present in all living cells. It acts as a messenger within the body, carrying genetic information from DNA to control the formation of proteins. Many viruses, such as SARS-CoV-2, encode their genetic information using RNA.

Proteins are the key building blocks of life and play critical roles in all living organisms. Being able to visualise them at the molecular level enables scientists to understand their function and how they work. This information is essential to identify potential targets for drugs and vaccine development.

A protease is an enzyme that helps to break down the long chainlike molecules of proteins into shorter fragments, called peptides. SARS-Cov-2 has 2 proteases. Both are essential for viral replication and are therefore attractive targets for drug discovery. Please note that Diamond is working on non-infectious samples.

We have the ability to purify the proteins that we know are the building blocks of the virus, but without the viral RNA that is responsible for their infectious nature. The viral RNA can be ‘stripped out’, leaving the rest of the virus to be analysed and the sample becomes non-infectious.

Each of the viral proteins in the virus has a specific function to allow the virus to infect cells and replicate. For example, the SARS-CoV-2 genome is encoded by RNA and this needs to be translated into DNA, which encodes the viral proteins. Many of these viral proteins are enzymes that are critical for RNA replication, others are important in releasing these enzymes so that they can carry out their functions, such as the proteases that are being worked on at Diamond. As these proteins have a critical role in the life cycle of the virus, structural biologists can target them to design compounds to inhibit their function. All enzymes have a specific location in the molecule that allow it to carry out its function, this is referred to as the ‘active site’. If we can block this site with other chemicals, the enzyme is unable to carry out its function. Alternatively, binding chemicals to other locations in the enzyme or protein can also affect the ability of the protein or enzyme to function effectively. Structural biologists use a library of small chemical compounds to begin the process of developing chemicals to bind to active sites. They mix these small compounds with the protein to see if any of them bind to the active sites. By determining the individual structures of each protein/compound mix, structural biologists can rapidly assess if any of these compounds bind to the protein and if so, where on the protein molecule. Each binding event between a protein and small chemical compound is described as a ‘hit’.

Each of these identified hit binding sites provides chemists with a starting point for developing a ‘key’ to lock into these sites, thus stopping the virus from functioning. SARS-CoV-2 potentially has many proteins that can be used as drug targets and the method described above for identifying chemical compounds that can be used for drug discovery can be applied to all of them.  By using small chemical ‘fragments’ to probe potential binding sites of the drug target, structural biologists and chemists highlight these compounds as potential foundation building blocks for the development of more complex and potent compounds. The drug targets being actively worked on at Diamond are the SARS-CoV-2 proteases that are essential for viral replication.

Small chemical fragments that hook in to hit binding sites are typically used by medicinal chemists to rapidly synthesise compounds that bind more strongly to the protein, to make them effective inhibitors of the protein (or virus) function. For example, in the case of SARS-CoV-2, if you can inhibit the function of the 2 viral proteases, this would be an effective way of inhibiting the virus from replication and could stop the virus from propagating and causing disease.

The structural data that are generated through determining a large number of virus structures with a large library of different chemical fragments provides essential information for computational and medicinal chemists to work with and speed up the drug development process.

Coronaviruses are a family of viruses that include the common cold, SARS, MERS etc. The current pandemic has been officially given the name COVID-19 by the World Health Organisation. COVID-19 stands for Coronavirus Disease 19, as it emerged in 2019. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is part of the coronavirus family and is the virus responsible for the COVID-19 disease. Viruses, and the diseases they cause, often have different names, for example HIV is the virus that causes AIDS. Viruses are often named based on their genetic structure and help the scientific community work on diagnostic tests, vaccines and medicines. Diseases are named to enable discussion on disease, spread, transmissibility, severity and treatment (WHO).

The response to COVID-19 has been remarkable; first reports of an unknown pneumonia were received on 31^st December 2019 and by 11^th January 2020 six virus sequences were made available. Structural biologists moved extraordinarily quickly, getting synthetic genes made immediately, rushing to pick them up the day they were finished, and in less than a month, on the 5^th Feb the first structure of the main protease was released by the Protein Data Bank (a global repository of protein data), from Zihe Rao and Haitao Yang's team at Shanghai Tech. By then these coordinates had already been distributed by the team to 300 groups around the world. Since then the response has truly been a global one. Diamond is proud to be a key contributor to the advancement of our knowledge on COVID-19 and you can find the latest updates on our ongoing work here.