Development of Improved Immunosuppressant Targeting Calcineurin – NFAT Protein – Protein Interaction Via Small Molecules and Peptides

Modern drugs are molecules that interfere with the activity of a specific protein related to a target disease. Within this realm, new molecules capable of interfering with protein-protein interactions (PPIs) are in the heart of modern drug discovery. However, the discovery or de-novo design of new molecules is often hampered by the lack of structural information of the PPI interfaces and suitable experimental binding techniques. This often prompted the conclusion that PPIs are “undruggable” targets. By fostering a multidisciplinary collaboration, we are able to identify new peptides and small molecules capable of interfering with PPIs. These are high affinity & specificity protein-protein interaction modulators.
This invention relates to immune signaling and specifically, the inhibition of calcineurin-NFAT interaction. Calcineurin is a protein phosphatase that regulates the initiation of the immune response. As such, calcineurin is an important target for immunosuppressive therapy. Although clinically approved drugs of calcineurin exist (Cyclosporine A and Tacrolimus), they have undesirable side effects such as nephrotoxicity and hepatotoxicity. Thus, the ongoing search for drugs that inhibit calcineurin with higher specificity and reduced toxicity is desired. However, the interaction of calcineurin with its substrates is structurally challenging, preventing the application of classical drug-discovery approaches.

Using our propriety algorithms and methods, we identified new small molecules and peptides capable of interfering with calcineurin-NFAT interaction. These molecules pave the way for the development of new therapeutics such as immunosuppressants (transplantations, psoriasis, and more).

The development of safe and effective orally available immune suppression drugs

Small molecules and peptides interfering with calcineurin protein-protein interactions

Immune suppressant
Immunological disorders (i.e., psoriasis)
Anti-fungal agents

In-vitro, new peptide and small molecule NCEs have been identified and characterized.

1. https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1010874

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