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Structure-Activity Relationships of Novel Tau Ligands: Passive Fibril Binders and Active Aggregation Inhibitors.

ABSTRACT: Intrinsically disordered proteins (IDPs) are core components of many biological processes and are central players in several pathologies. Despite being important drug targets, attempts to design small-molecule ligands that would help understand and attenuate their behavior are frustrated by the structural diversity exhibited by these flexible proteins. To accommodate the dynamic nature of IDPs, we developed a procedure that efficiently identifies active small-molecule ligands for disordered proteins. By exploring the chemical space around these ligands, we refined their effect on aggregation and identified molecular features critical for activity and affinity. Notably, the discovery of this new family of disordered protein ligands was achieved more quickly and with less expense than conventional high-throughput screening (HTS) or docking alone would have allowed. The resulting ligands include tau aggregation inhibitors as well as at least one compound that binds fibrils potently but does not appear to perturb the extent of kinetics of aggregation.

SUBMITTER: Baggett DW

PROVIDER: S-EPMC9381419 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Structure-Activity Relationships of Novel Tau Ligands: Passive Fibril Binders and Active Aggregation Inhibitors.

Baggett David W DW Nath Abhinav A

ACS chemical biology 20220211 3

Intrinsically disordered proteins (IDPs) are core components of many biological processes and are central players in several pathologies. Despite being important drug targets, attempts to design small-molecule ligands that would help understand and attenuate their behavior are frustrated by the structural diversity exhibited by these flexible proteins. To accommodate the dynamic nature of IDPs, we developed a procedure that efficiently identifies active small-molecule ligands for disordered prot ...[more]

PMID: 35147406

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Project description:Short peptide sequences within the microtubule binding domain of the protein Tau are proposed to be core nucleation sites for formation of amyloid fibrils displaying the paired helical filament (PHF) morphology characteristic of neurofibrillary tangles. To study the structure of these proposed nucleation sites, we analyzed the x-ray diffraction patterns from the assemblies formed by a variety of PHF/tau-related peptide constructs containing the motifs VQIINK (PHF6*) in the second repeat and VQIVYK (PHF6) in the third repeat of tau. Peptides included: tripeptide acetyl-VYK-amide (AcVYK), tetrapeptide acetyl-IVYK-amide (AcPHF4), hexapeptide acetyl-VQIVYK-amide (AcPHF6), and acetyl-GKVQIINKLDLSNVQKDNIKHGSVQIVYKPVDLSKVT-amide (AcTR4). All diffraction patterns showed reflections at spacings of 4.7 A, 3.8 A, and approximately 8-10 A, which are characteristic of an orthogonal unit cell of beta-sheets having dimensions a=9.4 A, b=6.6 A, and c=approximately 8-10 A (where a, b, and c are the lattice constants in the H-bonding, chain, and intersheet directions). The sharp 4.7 A reflections indicate that the beta-crystallites are likely to be elongated along the H-bonding direction and in a cross-beta conformation. The assembly of the AcTR4 peptide, which contains both the PHF6 and PHF6* motifs, consisted of twisted sheets, as indicated by a unique fanning of the diffuse equatorial scattering and meridional accentuation of the (210) reflection at 3.8 A spacing. The diffraction data for AcVYK, AcPHF4, and AcPHF6 all were consistent with approximately 50 A-wide tubular assemblies having double-walls, where beta-strands constitute the walls. In this structure, the peptides are H-bonded together in the fiber direction, and the intersheet direction is radial. The positive-charged lysine residues face the aqueous medium, and tyrosine-tyrosine aromatic interactions stabilize the intersheet (double-wall) layers. This particular contact, which may be involved in PHF fibril formation, is proposed here as a possible aromatic target for anti-tauopathy drugs.

Dataset Information

Structure-Activity Relationships of Novel Tau Ligands: Passive Fibril Binders and Active Aggregation Inhibitors.

Publications

Structure-Activity Relationships of Novel Tau Ligands: Passive Fibril Binders and Active Aggregation Inhibitors.

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