Gain Therapeutics Revolutionary Drug Discovery: Combining Physics, Biochemistry, and Supercomputing


Discovering treatments for patients that currently have no available disease-modifying options is the priority of Gain Therapeutics. Specifically, there is a large unmet need for patients suffering from protein misfolding disorders that alter enzyme function.

What is Gain Therapeutics approach to drug discovery?

The pipeline begins with Gain’s agnostic discovery platform for Site-Directed Enzyme Enhancement Therapy (SEE-Tx). This is a computational platform, as opposed to an artificial intelligence (AI) system. This is preferable for multiple reasons. First, AI needs a large amount of data while SEE-Tx starts with a 3D protein structure to find novel binding sites within the protein. SEE-Tx can use the already published 3D protein structures solved by cryo-EM, or alternatively, the platform can utilize 3D structural predictions from the AlphaFold Database. After the platform identifies new binding sites on a previously undruggable protein, it can also compute the druggability of the identified allosteric binding site using quantitative predictions as opposed to discovery approaches using AI technology that cannot be interpreted. Importantly, any targeted sites will allow for protein function to be restored without interfering with the active sites of the enzyme and its substrate.

How can lysosomal storage disorders be treated by allosteric binding?

Currently, the lead programs at Gain are focused on identifying targets and developing treatments for lysosomal storage disorders. Lysosomal storage diseases encompass dozens of metabolic disorders due the aberrant function of the lysosome. The lysosome is the garbage disposal of the cell made up of enzymes that work to break down compounds for later recycling or degradation. Sometimes, genetic mutations cause some of these key enzymes to be dysfunctional which leads to a buildup of toxic debris within the cells of various organs, depending on the disease. The goal is to restore the function of misfolded enzymes by targeting allosteric binding sites identified by the SEE-Tx drug discovery platform. SEE-Tx can then screen millions of compounds to select for a pool of molecules that are compatible with the binding site. This pool of selected noncompetitive pharmacological chaperones can then be tested for how good they are at increasing the efficiency of the defective enzyme. If the target enzyme has improved function, it will relieve the stress on the cell by cleaning up its intended debris and alleviating symptoms for patients.

Gain Therapeutics has 3 lead programs focused on Morquio B/GM1 Gangliosidosis, Gaucher disease, and Parkinson’s disease. Morquio B syndrome or GM1 Gangliosidosis are caused by mutations in the gene encoding beta-galactosidase (GLB1) while mutations in the gene encoding for beta-glucocerebrosidase (GBA1) cause Gaucher disease and are associated with Parkinson’s disease. All these diseases are associated with lysosomal dysfunction and the downstream effects of metabolic byproduct buildup.

The SEE-Tx platform is widely applicable

Gain is focused on lysosomal storage disorders to address the current medical need for patients, but the applicability of the SEE-Tx platform does not end there. Alterations to metabolism are involved in many diseases, including cancer. The drug discovery platform could be used to identify allosteric pharmacological molecules that can help inhibit or enhance the function of enzymes involved in various cancers. Aside from enzymes, allosteric binding could be used to target cancer-associated proteins and leave them marked for proteasomal degradation. Allostery opens the door for novel drug targets that could be used as a treatment alone or augment other cancer treatments like chemotherapy.

In addition to oncology, the SEE-Tx platform can be used to identify targets in neurodegenerative diseases. Many neurodegenerative disorders are caused by the misfolding and accumulation of a given protein. For example, in Parkinson’s disease, one driver of disease is the misfolding and accumulation of the protein alpha-synuclein. However, it is also appreciated that issues in the lysosome due to enzyme deficiency in beta-glucocerebrosidase can cause a lipid imbalance within the cell. This imbalance can make alpha-synuclein more prone to aggregation, increasing the likelihood of developing Parkinson’s disease. When it comes to treatment options, the SEE-Tx platform can target either the protein or the enzyme(s) involved in neurodegeneration. This prospect becomes particularly appealing for protein misfolding disorders where it may be possible to identify an allosteric binding site that could “lock” a misfolded protein and prevent it from continuing the misfolding cascade that eventually causes disease.

Drug discovery at Gain Therapeutics is currently focused on enhancing or rescuing enzyme activity to alleviate the symptoms of lysosomal storage disorders, but there are multiple strategies for allosteric regulation. These include enzyme inhibition or enhancement, inhibition of a nonenzymatic protein, or stabilizing a protein to prevent misfolding. The application of the SEE-Tx platform for lysosomal storage disorders is only the beginning of revolutionizing the landscape of therapeutic development. 

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