Invited
Conversion of protein active regions into peptidomimetic therapeutic leads

We developed various proprietary technologies for the conversion of proteins and peptides into drug candidates. These include: (1) "spatial screening" - development of N-methylated, end to end cyclohexapeptide combinatorial libraries for the selection of drug leads (2) "backbone cyclization" that confer metabolic stability and selectivity (3) "cycloscan" that include the design and synthesis of backbone cyclic peptide libraries with conformational diversity, and the selection of lead compound with drug-like properties (4) "Lipophilic Prodrug Charge Masking" (LPCM) that confer oral bioavailability on the selected leads.

The use of these technologies will be demonstrated in two cases: (1) development of an orally available N-methylated RGD containing cyclohexapeptide that selectively inhibit Integrin αVβ3. This compound was used as an adjuvant for "Vascular Promoting Chemotherapy" of resister cancers such as LLC and pancreatic cancer. (2) development of a selective inhibitor of Integrin α4/α9β1 (called visabron) that inhibit lymphocyte migration in autoimmune diseases. We have demonstrated the efficacy of visabron, in comparison with the Mab Tysabri, in curing multiple sclerosis (MS) in mice.

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A. Schumacher-Klinger et al. Molecular Pharmaceutics, 2018; 15 (8), 3468-3477