2 research outputs found
Diversity-Oriented Stapling Yields Intrinsically Cell-Penetrant Inducers of Autophagy
Autophagy
is an essential pathway by which cellular and foreign
material are degraded and recycled in eukaryotic cells. Induction
of autophagy is a promising approach for treating diverse human diseases,
including neurodegenerative disorders and infectious diseases. Here,
we report the use of a diversity-oriented stapling approach to produce
autophagy-inducing peptides that are intrinsically cell-penetrant.
These peptides induce autophagy at micromolar concentrations in vitro,
have aggregate-clearing activity in a cellular model of Huntington’s
disease, and induce autophagy in vivo. Unexpectedly, the solution
structure of the most potent stapled peptide, DD5-o, revealed an α-helical
conformation in methanol, stabilized by an unusual (<i>i</i>,<i>i</i>+3) staple which cross-links two d-amino
acids. We also developed a novel assay for cell penetration that reports
exclusively on cytosolic access and used it to quantitatively compare
the cell penetration of DD5-o and other autophagy-inducing peptides.
These new, cell-penetrant autophagy inducers and their molecular details
are critical advances in the effort to understand and control autophagy.
More broadly, diversity-oriented stapling may provide a promising
alternative to polycationic sequences as a means for rendering peptides
more cell-penetrant
Legislative Documents
Also, variously referred to as: House bills; House documents; House legislative documents; legislative documents; General Court documents