Structural biology guiding development of new SARS-Cov2 therapies

After entering a host cell, the SARS-CoV2 virus begins to replicate and changes the host cell into a virus factory. For this to happen, the virus requires synthesis of new viral proteins that are formed at the endoplasmic reticulum, a part of the human cell endomembrane system. 

Academy Research Fellow Ville Paavilainen's laboratory focuses on studying how cells maintain a healthy protein balance and how the complicated multistep process of protein secretion is achieved.

– All of the proteins in a cell together form each cell’s unique proteome, which determines the identity and function of different cells. This proteome is dynamic; at any given time, cells both form new proteins and destroy old ones, which creates a dynamic balance. This protein balance is an important property of cells and is known to be disturbed in diseases such as cancers and targeting factors contributing to maintenance of protein balance is an important therapeutic strategy, says Paavilainen.

The laboratory has already studied small molecules that disturb replication of influenza and zika virus and are also promising candidates for development of mechanistically unique cancer therapies. Unexpectedly, now researchers have found that the same molecules can also act as a lead compound against SARS-CoV2.

– We already know that these small molecules are effective against SARS-CoV2 in cell culture models, and animal testing is about to begin. In addition, research into these molecules as possible cancer treatments is close to entering human testing, which means that it will also be possible to proceed quickly with human testing in their use for SARS-CoV2 if these molecules appear promising and are found to be sufficiently safe. 

A familiar molecule from studies in California

– This molecular family, the cotransins, was already my research subject during my postdoctoral research in California. The original form of cotransins is found in nature, being produced by an endosymbiotic fungi that associates with plant roots. This molecule was originally found in a screen for inhibitors of human cell adhesion protein expression. Later, we showed that this molecule prevents protein secretion with an entirely unique mechanism. Contrary to conventional protein inhibitors that typically block the enzymatic activity of a disease-associated protein, cotransins prevent their biogenesis by preventing their entry into the protein secretion pathway, says Paavilainen.  

Based on these studies, a company, Kezar Life Sciences, has been established in San Francisco, and they are pursuing development of cotransins as novel cancer therapies. Paavilainen’s research group is currently working with Kezar to understand the mechanism of cotransin activity and to develop improved cotransin variants.

Structural biology as a tool in drug discovery

Structural biology is a branch of molecular biology, which focuses on studying the structure of biological macromolecules such as proteins, and this knowledge helps in understanding the functioning of molecules.

– We use structural biology to study the atomic level interactions that enable formation of certain classes of proteins, such as secreted proteins and integral membrane proteins such as cell surface signaling receptores. Often, seeing how factors influencing cellular protein balance interact with one another and small molecules that bind them can provide important mechanistic insights into their physiological functions and small molecule interactions, explains Paavilainen.

Structure-based drug design refers to all methods of structural characterization that provide an atomic level view of how therapeutic leads such as small molecules interact with their target proteins. Direct visualization of these small molecule interactions then allows medicinal chemists to rationally design new small molecule variants, which often leads to large improvements in effectiveness and drug like-properties of the resulting new inhibitors. 

– Structure-based drug design has revolutionized the optimization of drug molecules compared to a time when structures of for example many cell surface receptors were unknown.

High computing performance required

In March, CSC opened a prioritized access to Puhti supercomputer for COVID-19 pandemic research and Paavilainen’s laboratory is one of the groups chosen to this fast track.

– A method called cryo-electron microscopy (cryo-EM) has revolutionized structural biology in recent years.  However, its use in structure-based pharmaceutical development is still new. A large number of particle projection images, often several million, collected in multiuser cryo-EM facilities either locally or abroad, are used to determine the structure of the macromolecule in question. The data processing requires massive data storage and high performance computing, explains Juha Huiskonen, Associate Professor at the University of Helsinki, who collaborates with Paavilainen.

– We use established software such as RELION and CryoSPARC, which are installed on CSC’s Puhti server. The first models we have calculated on Puhti are accurate enough to see small molecules and even individual water molecules interacting with the protein of interest. Mahti supercomputer is expected to allow even larger computations, which will be required to follow how the protein is moving in solution, he continues. 

– With the help of CSC’s HPC infrastructure, we expect to determine how potential drug molecules shut down expression of SARS-CoV-2 enveloped proteins, summarizes Paavilainen. 

– This study is a perfect example of how fundamental basic science research that is often non-directed and driven by personal curiosity and desire to understand a physical or biological system can lead to an immediate translational use, says Postdoctoral fellow Shahid Rehan, the lead author of this work. 
 

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