Macrocyclic modulators of disease associated protein misfolding and aggregation
AssigneeResq Biotech
InventorGeorgios Skretas
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Abstract
Aspects of the present invention disclose compounds that modulate the aggregation of amyloidogenic proteins or peptides. In some aspects, disclosed compounds modulate the aggregation of disease-associated proteins and natural β-amyloid peptides. In a preferred embodiment, the compounds can inhibit natural amyloid aggregation. Pharmaceutical compositions comprising the compounds of the embodiments, and diagnostic and treatment methods for diseases (e.g., amyloidogenic diseases) using the compounds, are also disclosed. In addition, there is provided an integrated bacterial platform for the discovery of rescuers of disease-associated protein misfolding.
Claims11
A method of identifying modulators of a misfolding-prone protein associated with a protein misfolding disease, comprising:
- (A) obtaining a population of transformed bacterial cells that co-express:
- (a) a nucleic acid encoding a library of peptide macrocycles, operably linked to a promoter and;
- (b) a bipartite nucleic acid comprising a sequence for a gene encoding a misfolding-prone protein associated with a protein misfolding disease (MisP) and a sequence encoding a protein reporter;
- (B) identifying bacterial cells of step (A) that exhibit enhanced levels of protein reporter activity, as measured by a detectable output indicative of reporter function;
- and
- (C) identifying the bioactive peptide macrocycles in the library that modulate MisP misfolding.
Dependencies are inferred from the claim text.