Design av kemiska verktyg för utveckling av läkemedel bortom ¨regeln om 5¨

Tidsperiod: 2017-01-01 till 2020-12-31

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 200 000 SEK

Many novel targets, in particular protein-protein interactions (PPIs), cannot be modulated with small drug-like molecules. Instead, compounds in a different chemical space, e.g. macrocycles and peptides, are required. This research program deals with how ligands for difficult targets should be designed, and their subsequent use in studies of molecular recognition in three related projects.- We have challenged the dogma that drugs must obey Lipinski’s rule of 5 (Ro5) and have deduced guidelines for design of compounds far beyond the Ro5 (bRo5) that combine potent binding to difficult targets with cell permeability. We will now develop predictive models for cell permeability in bRo5 space and design compounds that modulate PPIs involved in e.g. cancer and atherosclerosis.- C-peptide has beneficial effects in chronic kidney disease (CKD) and we will use state of the art imaging and biochemical techniques to determine its mechanism of action, then decide if C-peptide is of interest for further studies of CKD.- We have found that a glycopeptide from type II collagen (CII) has a key role in pathogenesis of rheumatoid arthritis (RA), and that it can be used to cure disease in a mouse model. Recent results also suggest that antibody recognition of epitopes on cartilage proteins, like CII, may be predictive for development of RA. We will now develop glycopeptide-based vaccines to treat RA and diagnostics based on synthetic mini-CII proteins fo