Drug Discovery Case Studies

Exploring novel antibodies to neutralise the RBD of SARS-CoV-2

The COVID-19 virus pandemic caused by the SARS-CoV-2 coronavirus poses an ongoing serious global health threat that requires effective and safe therapeutics. The SARS-CoV-2 coronavirus uses its spike glycoprotein to bind to the host receptor angiotensin-converting enzyme-2 (ACE-2) and enter the body’s cells.

The receptor-binding domain (RBD) of the spike glycoprotein is the main target for neutralising antibodies as it can block the virus-host interaction and prevent the infection. The RBD is highly variable and can mutate to escape recognition by antibodies, thus reducing their efficacy and increasing the risk of resistance.

Moreover, the RBD is only exposed transiently on the spike glycoprotein, making it difficult for antibodies to access and bind to it. Novel antibodies are needed that can recognise and neutralise the RBD of SARS-CoV-2 with high potency and stability, regardless of its variability and accessibility

Structure of a FAB-PD1 complex

Programmed Cell Death Protein 1 (PD1) is a receptor protein on the surface of T cells which is involved in the suppression of the immune system. Blocking PD1 has been a successful approach to enhance anti-cancer immune responses, and there is also significant interest in developing molecules that can trigger PD1 signalling to treat autoimmune diseases.

Using Diamond's XChem platform to study the structure of proteins in SARS-CoV-2

Following the emergence of the new coronavirus SARS-CoV-2 in late 2019 which quickly developed into a pandemic, the race soon began to discover more about the virus and prevent its spread. 

Building on the knowledge gained from the SARS outbreak in 2003, it is hoped that by studying the structure of the proteins in SARS-CoV-2 scientists will identify potential lead compounds and develop therapies to prevent viral infection and replication.

Triggering a natural defence system for cancer immunotherapy

T-cell receptors (TCRs) are protein complexes found on the surface
of human T-cells responsible for recognising a large variety of
antigen peptides. When a TCR binds to a specific antigen it triggers
an immune response that is part of the adaptive immune system
and prevents the growth of pathogens.

There is great interest in using this natural defence system for
cancer immunotherapy by producing modified TCRs that bind
cancer antigens and activate an immune response against
tumours.

LCP-FRAP - a valuable tool to accelerate membrane protein projects

Membrane proteins represent a large group of important drug targets with over 50% of approved drugs targeting these proteins within the body.
Understanding the 3D structure of membrane proteins is invaluable for target discovery, validation, and for hit optimisation. X-ray macromolecular crystallography (MX) is a principal research method for acquiring structural information on membrane proteins, but for this to be successful we require the production of good quality crystals from the target protein, or its complexes with potential drug candidates.

It is particularly difficult to produce and purify membrane proteins in sufficient yield and quality for crystallisation, and furthermore, membrane protein crystallisation itself represents a significant challenge.

A new approach to inhibit the flu virus

The World Health Organization estimates that worldwide, annual influenza epidemics result in about 3-5 million cases of severe illness and about 250,000 to 500,000 deaths. Influenza A viruses are the most common cause of seasonal flu in humans and represent a significant risk to public health.

When the influenza virus infects a host cell, it starts to make copies of itself as the disease spreads. The protein driving this behaviour is the viral RNA polymerase which replicates the viral RNA genome and makes RNA templates for protein synthesis. In order to understand how this process works, you need to work out the structure of the RNA polymerase at the atomic level.

Tuning hormone production at a molecular level to treat patients with thyroid conditions

The thyroid is a gland located in our neck which produces iodinated hormones essential for metabolism and growth, namely thyroid hormones (TH). 

An imbalance in thyroid hormone production may lead to a range of disorders including cardiovascular, foetal development, and psychiatric problems, which affect more than 5% of the population worldwide, with increasing incidence. Most commonly, people suffer from an under-active thyroid (hypothyroidism) or less frequently, an over-active thyroid (hyperthyroidism). These conditions are often related to thyroid auto-immunity and cancer. 

Personalising alendronate therapy when treating Osteoporosis

Osteoporosis is a bone disease that affects 200 million people worldwide and contributes to 8.9 million fractures annually. The condition causes a loss of bone mass and structure which in turn leads to bones becoming weak and breaking, usually during a trip or fall. The disease is prevalent in people over 55, and in particular women, due to the loss of oestrogen hormone during the menopause. Osteoporosis is becoming increasingly prevalent in men who receive cancer therapies which supress testosterone levels. Bisphosphonates are a family of medicines which are commonly prescribed to treat osteoporosis. The most common types are alendronate and zoledronate which aim to strengthen osteoporotic bones by slowing down the activity of bone cells.

Setting the foundation for new anti-malaria drugs

Malaria is one of the most prevalent parasitic diseases of humans and affects 216 million people worldwide. Many years of research have been dedicated to finding the most effective and affordable drugs to prevent infection, which have to date been very successful.  Most recently the challenge has been the growth in resistance to existing treatments, which has driven further research into a new generation of anti-malarial drugs.

Mechanical Properties of Bacteria

Antibiotic resistance is an increasingly serious threat to global public health that requires action across all government sectors and society. There are high proportions of antibiotic resistance in bacteria that cause common infections, for example urinary tract infections, and it is patients with these infections caused by drug-resistant bacteria that are generally at increased risk of worse clinical outcomes and death. These patients consume more health-care resources than patients infected with the same bacteria that are drug-resistant. Developing new treatments to tackle this worldwide problem is therefore of paramount importance.

Tackling antibiotic resistance

Respiratory infections are one of the biggest killers in the western world, and pneumococcal infections can range from mild to potentially deadly. Children and the elderly are most at risk, as well as those with compromised immune systems. There are approximately 90 distinct pneumococcal serotypes and, although not all cause disease, this makes treatment challenging. An effective conjugate vaccine has been available since 2001, however there has been a rise in antibiotic resistance in serotypes not covered by this conjugate vaccine and previously non-infectious serotypes are increasing in virulence. This makes treatment of pneumococcal pneumonia and less severe illnesses such as otitis media more difficult to manage. Therefore finding new approaches to combat pneumococcal disease remains a high priority.

The ABCs of flu

Influenza viruses altogether affect 5%-10% of the adult population and 20-30% of children each year. These annual epidemics are estimated to result in about approximately 3 to 5 million cases of severe illness, leading to between 250,000 to 500,000 deaths around the world. Integral to viral replication, polymerases are enzymes that copy the viral genome and produce messenger RNA which is then used to make building blocks for new virus particles.

Auto-processing software pipelines at Diamond’s MX beamlines

As fast Pilatus detectors have become the gold standard at Diamond’s MX beamlines, the time needed for collecting a complete dataset is now less than two minutes. This gives a user very limited time to process data and subsequently decide what would be the best strategy for collection of data from remaining crystals.

In crystallo fragment screening

In the past two decades, fragment based drug discovery has emerged as a powerful method to discover and develop new drugs. Such strategy relies on the identification of low molecular weight compounds that bind weakly to a target. The structural information gained on fragment-target complexes provides an excellent starting point for the development of potent and selective drugs.

Xanthine-GPCR binding structures herald new Parkinson's treatments

Methylxanthines, including caffeine, theophylline (found in tea), and theobromine (a constituent of chocolate) are among the most widely consumed substances in the world, but their effects on the brain are not fully understood. Previously published research has shown a correlation between higher intake of caffeine and lower incidence of Parkinson’s disease. Adenosine A_2A receptors regulate the effects of neurotransmitters in the brain, cardiovascular and immune systems, and are of particular interest as a drug target.

Mail-in data collection service for MX at Diamond

Fragment-based and structure-based drug discovery programmes put a strong emphasis on frequent routine macromolecular crystallography data collection from numerous samples. Other types of projects may only need occasional data collection on a few samples or researchers may need to run an experiment they have not done before. 

Creating crystals: out of this world!

X-ray structural investigation of macromolecules (proteins, viruses, enzymes etc) is a complex and time consuming process where the quality of information obtained about the three-dimensional structure is strongly dependent on the quality of crystals produced. Therefore, the structures of many important targets of pharmaceutical and biotechnology industry remain unknown simply because researchers are unable to obtain crystals of sufficiently high quality or size.

Using MX at Diamond to solve structures relevant to inherited disease

Huntington’s disease (HD) is a dominantly-inherited neuropsychiatric disorder which causes severe motor dysfunction, depression and dementia. It has been known since 1993 that the disease is due to mutation of a single gene coding for huntingtin (HTT) that extends the poly-glutamine (poly-Q) repeats in the protein. Inhibiting the enzyme responsible for the cleavage of mutant HTT - thereby reducing the generation of the poly-Q fragments - could be one way of preventing neurodegeneration. Caspase-6 was identified as this processing enzyme, yet, while structures of other caspase enzymes have been studied, caspase-6 has been suggested to be this processing enzyme but, while structures of other caspase enzymes have been solved.

High throughput macromolecular crystallography

Macromolecular crystallography (MX) is a key asset in the development of new drugs via structure based drug discovery. This process is now widely used by the pharmaceutical industry to gain structural insights into drug targets and map interactions with ligands. However, isolating and optimising a new lead compound is a time consuming process which usually involves screening hundreds of samples.

Tropoelastin: nature's perfect nanoscale spring

Elastin allows tissues in humans and other mammals to stretch and return to original shape e.g. during respiration or heart beats. The schematic on the right shows how many tropoelastin monomers (blue) can selfassemble and cross-link (red) to form elastin but the structure of the soluble precursor of elastin, tropoelastin, is not well understood.

Grid scan technique for fast crystal detection and characterisation

Developments on macromolecular crystallography (MX) beamlines have achieved very high throughput and microfocus X-ray facilities have made it possible to successfully collect diffraction data from samples previously considered too small or too disordered. However, when the use of microfocus beams is coupled with the small size and poor optical properties of some samples, sample alignment and detection becomes a key problem.

In situ macromolecular crystallography: room temperature screening and data collection

The size and diffraction quality of crystals remain the major limiting factors of macromolecular crystallography (MX). Many crystals of challenging targets are small, weakly diffracting and indeed extremely sensitive to manual handling. The time consuming and often damaging process of cryo-protecting, mounting and cryocooling of crystals can significantly decrease the crystal order, resolution and overall quality of the data.

HC1: a user-friendly device for crystal dehydration

Investigating the 3D structure of macromolecules by X-ray crystallography requires the production of high quality crystals, and yet this step remains a tedious and empirical task. Weak packing and high solvent content are among the most frequent factors causing a negative impact on the acquisition of suitable diffraction images. It is, therefore, useful to develop post-crystallisation methods to enhance crystal quality.

Collect your MX data from anywhere using Remote Access at Diamond

Fragment-based and structure-based drug discovery projects require regular and frequent proprietary access to macromolecular crystallography (MX) beamlines at synchrotron facilities. However, geographic location, shutdown periods, limited human resources and beamtime availability can restrict the access to such facilities.