But then we had a surprise – cana and a related inhibitor also profoundly change the final structure of amyloid fibrils.

This suggests that early events in amyloid formation are crucial for determining the subsequent structures of fibril polymorphs.

(4/6)

10.04.2025 15:17 — 👍 1    🔁 1    💬 1    📌 0

Thrilled to share our new paper on the front cover of JACS! 🧪💊🍾

Kinetic inhibitors of the early steps of #amyloid formation can profoundly affect the resulting fibril polymorphism – suggesting a new strategy to treat protein aggregation diseases.

🔗 pubs.acs.org/doi/10.1021/...

🧵... (1/6)

10.04.2025 15:17 — 👍 2    🔁 2    💬 1    📌 0

Picture

At last our paper is out at JACS and we made the front cover! Thanks to Phospho animation for the image. See doi.org/10.1021/jacs....

10.04.2025 14:13 — 👍 3    🔁 3    💬 0    📌 0

The architecture of amyloid fibrils formed by a human tau-derived hexapeptide VQIVYK https://www.biorxiv.org/content/10.1101/2025.03.11.642642v1

12.03.2025 15:50 — 👍 2    🔁 2    💬 0    📌 0

Proud to be part of this great article with @ldaubrey.bsky.social . Of interest to all working on amyloid polymorphs see doi.org/10.1016/j.jmb.2025.169008

02.03.2025 12:21 — 👍 8    🔁 3    💬 0    📌 0

Thought-provoking and insightful new review on #amyloid fibril polymorphism by @ldaubrey.bsky.social and @radford-lab.bsky.social, with a useful simulation Colab alongside it (CoFiSim ☕👨‍💻). A must-read for those interested in how fibril polymorphs form, and why certain polymorphs dominate in vivo!

28.02.2025 17:10 — 👍 2    🔁 2    💬 0    📌 0

I realised it would be easier to show (than tell) some of this so I made CoFiSim, which simulates the fibril assembly (by numerically integrating rate equations) of 2 structures with independent rate constants competing for the same pool of monomer colab.research.google.com/drive/1DTCco...

28.02.2025 11:41 — 👍 0    🔁 0    💬 0    📌 0

I wrote down my thoughts about amyloid fibrils and how the mechanisms of fibril assembly might contribute to structural polymorphism in a review. Sheena @radford-lab.bsky.social liked it, made some improvements including adding some thoughts of her own and now here it is:

doi.org/10.1016/j.jm...

28.02.2025 11:41 — 👍 2    🔁 0    💬 1    📌 1

Kinetic Steering of Amyloid Formation and Polymorphism by Canagliflozin, a Type-2 Diabetes Drug Amyloid formation is involved in widespread health conditions such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. Amyloid fibrils have a similar cross-β architecture, but fibrils formed by a single protein sequence can have diverse structures, varying with time, self-assembly conditions, and sequence modifications. Fibril structure has been proposed to be diagnostic of disease, but why different structures result under different conditions, especially in vitro, remains elusive. We previously identified a small molecule, YX-I-1, which inhibits in vitro amyloid formation by islet amyloid polypeptide (IAPP), a peptide hormone whose amyloid formation is involved in type-2 diabetes. Here, using YX-I-1 as a lead, we identified regulator-approved drugs with similar structures by chemical similarity analysis and substructure searches and monitored the effect of 24 of these potential ligands on IAPP amyloid assembly in vitro. We show that one such compound, canagliflozin (Invokana), a type-2 diabetes drug already in clinical use, can strongly delay the kinetics of IAPP amyloid formation, an activity independent of its intended mode of action [sodium-glucose linked transporter 2 (SGLT2) inhibitor] that may have important therapeutic implications. Combining analysis of amyloid self-assembly kinetics, biophysical characterization of monomer and fibril binding, and cryo-EM of the assembly products, we show that YX-I-1 and canagliflozin target IAPP early in aggregation, remodeling the energy landscape of primary nucleation and profoundly altering the resulting fibril structures. Early binding events thus imprint long-lasting effects on the amyloid structures that form.

Suspect timing of @alextaylor314.bsky.social joining. It's almost like he's only here to see if anyone's talking about his excellent new JACS paper! doi.org/10.1021/jacs...

26.02.2025 10:32 — 👍 3    🔁 1    💬 0    📌 0

Hello all in Bluesky. The RadfordLab and friends will be posting here so please look out for our updates. We wish you all well for 2025!

31.12.2024 17:51 — 👍 13    🔁 3    💬 2    📌 1