Periodic Reporting for period 1 - SUCZYME (VALORISATION AND OPTIMIZATION OF NOVEL FIRST-IN CLASS SUCCINATE-DEPLETING THERAPIES)
Reporting period: 2023-07-01 to 2024-01-31
SUCCIPRO is a young company focused on the early development of succinate-modulating therapies. WomenTEchEU project has been focused on essential technical and business activities needed to de-risk the asset SUCZYME, a novel first-in-class oral gut-restricted enzyme therapy able to deplete succinate that has Crohn’s
Disease as a first indication. Drug development is a high risk activity and the project has been focused on advancing on the development of our drug candidates and increasing our visibility and our network with the ultimate goal of improving the TRL level of the asset and attract private investment.
Disease as a first indication. Drug development is a high risk activity and the project has been focused on advancing on the development of our drug candidates and increasing our visibility and our network with the ultimate goal of improving the TRL level of the asset and attract private investment.
At scientific and technical level we have combined in silico and in vitro methods to advance in the optimization of our drug candidates and we have also generated in vivo data.
In the field of therapeutic enzymes, drug optimization involves the amelioration of different attributes (i.e activity, stability) through the generation of enzyme variants. Accordingly, during the project we have done an in silico analysis to identify key residues of our main enzyme candidate. The in silico analysis has been based on available X ray structures which have been used to built dimer models in different conformations in which we have docked succinate, extracted the binding energies and clustered the docked conformations for succinate to identify credible binding modes. The analysis has allowed us to identify residues directly involved in the binding of succinate. Co-evolution patterns have also been analyzed to identify other targetable positions. As expected, this in silico analysis has led to generate a list of variants ranked based on sequence, evolutionary scoring, structure-based AI scoring and a biophysic-based scoring
A final set of 300 mutants were selected from which 240 were successfully cloned and produced.
Variants were tested in vitro through a custom enzymatic assay.
Whereas in the initial plan the idea was to test a selection of the best new variants in vivo, the optimization of candidates took longer than expected and, given the importance of generating compelling and timely data for investors, we decided to test in vivo two of our initial candidates instead of one of the new generated variants. Accordingly, by the end of the project we tested in vivo these two candidates in a mouse model of diet-induced Non-Alcoholic Fattly liver Disease and DSS-induced Inflammatory bowel Disease.
In the field of therapeutic enzymes, drug optimization involves the amelioration of different attributes (i.e activity, stability) through the generation of enzyme variants. Accordingly, during the project we have done an in silico analysis to identify key residues of our main enzyme candidate. The in silico analysis has been based on available X ray structures which have been used to built dimer models in different conformations in which we have docked succinate, extracted the binding energies and clustered the docked conformations for succinate to identify credible binding modes. The analysis has allowed us to identify residues directly involved in the binding of succinate. Co-evolution patterns have also been analyzed to identify other targetable positions. As expected, this in silico analysis has led to generate a list of variants ranked based on sequence, evolutionary scoring, structure-based AI scoring and a biophysic-based scoring
A final set of 300 mutants were selected from which 240 were successfully cloned and produced.
Variants were tested in vitro through a custom enzymatic assay.
Whereas in the initial plan the idea was to test a selection of the best new variants in vivo, the optimization of candidates took longer than expected and, given the importance of generating compelling and timely data for investors, we decided to test in vivo two of our initial candidates instead of one of the new generated variants. Accordingly, by the end of the project we tested in vivo these two candidates in a mouse model of diet-induced Non-Alcoholic Fattly liver Disease and DSS-induced Inflammatory bowel Disease.
This project has been focused on developing first steps of innovative therapeutic strategies based on engineered enzymes for treating metabolic and inflammatory diseases. These interventions advance precision medicine offering tailored solutions for individuals exhibiting elevated succinate levels refractory to conventional treatments. Manipulating specific metabolites may enhance therapeutic efficacy while minimizing off-target side effects associated to the full blockage of certain receptors or signalling pathways. Moreover, gut-restricted therapies offer advantages over systemic treatments by reducing systemic toxicity and are suitable for long-term administration in chronic conditions. Oral administration improves convenience and adherence, particularly in diseases like IBD. Also, these advancements in knowledge have the potential to pave the way for future investigations targeting other metabolites associated with disturbances in metabolic equilibrium. Furthermore, the insights gained from this research could potentially extend beyond its immediate scope and hold promise for addressing other diseases where succinate plays a critical role, including autoimmune disorders and cancer.
This project has set the stage for a novel first-in-class gut-restricted enzyme therapy for inflammatory and metabolic disorders, but further research is still needed to further improve its stability (i.e through proposing new mutations and/or formulating) and demonstrate its full potential in vivo. Moreover, at a later stage the compound will need to go through the preclinical and clinical regulatory phases. Given the unique mechanism of action of our first-in-class therapies, our research findings may inform regulatory bodies' evaluation of novel treatments and policy development for managing metabolic and inflammatory diseases. Since there are not current any drug directly modulating a metabolite, the preclinical regulatory phase, and in particular the toxicity studies, will be key. Regulatory agencies will wield significant influence over the business landscape, shaping various facets of our project, from production to marketing. Their role is crucial for the successful development of our products.
This project has set the stage for a novel first-in-class gut-restricted enzyme therapy for inflammatory and metabolic disorders, but further research is still needed to further improve its stability (i.e through proposing new mutations and/or formulating) and demonstrate its full potential in vivo. Moreover, at a later stage the compound will need to go through the preclinical and clinical regulatory phases. Given the unique mechanism of action of our first-in-class therapies, our research findings may inform regulatory bodies' evaluation of novel treatments and policy development for managing metabolic and inflammatory diseases. Since there are not current any drug directly modulating a metabolite, the preclinical regulatory phase, and in particular the toxicity studies, will be key. Regulatory agencies will wield significant influence over the business landscape, shaping various facets of our project, from production to marketing. Their role is crucial for the successful development of our products.