Inhibition of BACE1 and amyloid β aggregation by polyketide from Streptomyces sp

Chem Biol Drug Des. 2022 Feb;99(2):264-276. doi: 10.1111/cbdd.13980. Epub 2021 Nov 22.

Abstract

Alzheimer's disease (AD) causes cognitive impairment in the elderly and is a severe problem worldwide. One of the major reasons for the pathogenesis of AD is thought to be due to the accumulation of amyloid beta (Aβ) peptides that result in neuronal cell death in the brain. In this study, bioassay-guided fractionation was performed to develop seed compounds for anti-AD drugs that can act as dual inhibitors of BACE1 and Aβ aggregation from secondary metabolites produced by Streptomyces sp. To improve the solubility, the crude extracts were methylated with trimethylsilyl (TMS) diazomethane and then purified to yield polyketides 1-5, including the new compound 1. We synthesized the compounds 6 and 7 (original compounds 2 and 3, respectively), and their activities were evaluated. KS-619-1, the demethylated form of 4 and 5, was isolated and evaluated for its inhibitory activity. The IC50 values for BACE1 and Aβ aggregation were found to be 0.48 and 1.1 μM, respectively, indicating that KS-619-1 could be a lead compound for the development of therapeutic agents for AD.

Keywords: Alzheimer's disease; Streptomyces sp.; dual inhibitor; polyketide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Culture Media
  • Drug Evaluation, Preclinical
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Inhibitory Concentration 50
  • Polyketides / pharmacology*
  • Spectrum Analysis / methods
  • Streptomyces / metabolism*

Substances

  • Amyloid beta-Peptides
  • Culture Media
  • Polyketides
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human