Biology subjects

Matthes, D.

Publications and source records attributed to Matthes, D..

3 recordsLinked to original sources

bioRxiv2025

The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ fibrils and modulates fibril formation.

Alzheimers disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (A{beta}) fibrils. Therapeutic antibodies can slow down the disease, but are associated with potential severe side effects, motivating the development of small molecules to halt disease progression. This study investigates the interaction between the clinical drug candidate small molecule anle138b and lipidic A{beta}40 fibrils of type 1 (L1). L1 fibrils were previously shown to closely resemble fibrils from Alzheimers patients18. Using high-resolution structural biology techniques, including cryo-electron microscopy (cryo-EM), nuclear magnetic resonance (NMR) spectroscopy enhanced by dynamic nuclear polarization (DNP), and molecular dynamics (MD) simulations, we find that anle138b selectively binds to a cavity within the fibril. This structural insight provides a deeper understanding of a potential drug-binding mechanism at the atomic level and may inform the development of novel therapies and diagnostic approaches. In addition, anle138b reduces fibril formation in the presence of lipids by approximately 75%. This may suggest a mechanistic connection to its previously reported activity in animal models of Alzheimers disease15.

biochemistry↗

bioRxiv2025

Structural insight into binding of novel PET tracer MODAG-005 to lipidic ????-Synuclein fibrils

Accumulation of -synuclein (Syn) aggregates in the human brain is the major hallmark of synucleinopathies such as Parkinsons Disease, Multiple System Atrophy, and Dementia with Lewy bodies. Positron Emission Tomography (PET) plays a vital role in diagnosing these diseases and monitoring their progression by enabling the non-invasive and sensitive detection of Syn aggregates in the brain. However, developing PET tracers with specific target binding, as well as identifying the binding site and complex structure present significant challenges. Here, we investigated the interaction between lipidic Syn aggregates and MODAG-005, a new Syn PET tracer candidate, using nuclear magnetic resonance spectroscopy, cryogenic electron microscopy and molecular dynamics (MD) simulations. Two binding sites of MODAG-005 were found, one on the surface and one in a tubular cavity of the fibril, of which the occupancies were found to depend on the preparation protocols. The cavity binding site is thermodynamically more stable than the external binding site and is the only site occupied when MODAG-005 is applied with liposome as carriers to the aggregates. This is corroborated by MD simulations in which stable interactions between MODAG-005 and glycine containing backbone motifs of the tubular cavity of the aggregates are observed.

biochemistry↗

bioRxiv2022

The 3D structure of lipidic fibrils of α-synuclein

-synuclein (Syn) is abundant in neurons, but its misfolding and abnormal fibrillization are associated with severe neurodegenerative diseases. Although interactions between Syn and phospholipid membranes are relevant during Syn fibril assembly, insights into the interactions of Syn fibrils with phospholipids have remained elusive. Here, we present six novel polymorphic atomic structures of Syn fibrils aggregated in the presence of phospholipids. The structures reveal that phospholipids favor a novel protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities between the protofilaments. These findings provide a structural rationale for fibril-induced lipid extraction, a mechanism likely to be involved in the development of -synucleinopathies.

molecular biology↗