Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation
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Curated by eLife
eLife assessment
This study provides a valuable contribution to the development of small molecules that inhibit the aggregation of tau, a protein involved in several neurodegenerative diseases. The authors present convincing evidence that analogs of the plant alkaloid tryptanthrin can prevent the formation of larger aggregates by targeting the early stages of tau oligomerization. Nevertheless, further studies are needed to elucidate the precise mechanisms of action and to provide a detailed kinetic analysis. This work will be of interest to biochemists and biophysicists focused on designing small molecules to inhibit fibril formation.
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Abstract
Microtubule-associated protein tau is an intrinsically disordered protein (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which is Alzheimer’s disease (AD). Despite keen interest in disrupting or inhibiting tau aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This is due, in part, to the fact that tau and other IDPs do not exhibit a single well-defined conformation but instead populate a fluctuating conformational ensemble that precludes finding a stable “druggable” pocket. Despite this challenge, we previously reported the discovery of two novel families of tau ligands, including a class of aggregation inhibitors, identified through a protocol that combines molecular dynamics, structural analysis, and machine learning. Here we extend our exploration of tau druggability with the identification of tryptanthrin and its analogs as potent, substoichiometric aggregation inhibitors, with the best compounds showing potencies in the low nanomolar range even at a ∼100-fold molar excess of tau4RD. Moreover, conservative changes in small molecule structure can have large impacts on inhibitory potency, demonstrating that similar structure-activity relationship (SAR) principles as used for traditional drug development also apply to tau and potentially to other IDPs.
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eLife assessment
This study provides a valuable contribution to the development of small molecules that inhibit the aggregation of tau, a protein involved in several neurodegenerative diseases. The authors present convincing evidence that analogs of the plant alkaloid tryptanthrin can prevent the formation of larger aggregates by targeting the early stages of tau oligomerization. Nevertheless, further studies are needed to elucidate the precise mechanisms of action and to provide a detailed kinetic analysis. This work will be of interest to biochemists and biophysicists focused on designing small molecules to inhibit fibril formation.
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Reviewer #1 (Public Review):
Summary:
This paper presents a class of small molecule inhibitors of tau aggregation which was discovered through a computational screen. Analogs were generated and tested for their ability to inhibit fibril formation.
Strengths:
A few of the analogs were found to have sub-stoichiometric activity. A comparison of unseeded and seeded aggregation kinetics suggests that these compounds preferentially target early-stage aggregation.
Weaknesses:
The authors state their interest is in finding compounds that target monomeric states of tau, but their only detection method is late-stage fibril formation. In this respect, they have not really defined a mechanism of action. They state their plan to use hydrogen-exchange mass spectrometry, but there are other techniques, such as single-molecule FRET and measurement of …
Reviewer #1 (Public Review):
Summary:
This paper presents a class of small molecule inhibitors of tau aggregation which was discovered through a computational screen. Analogs were generated and tested for their ability to inhibit fibril formation.
Strengths:
A few of the analogs were found to have sub-stoichiometric activity. A comparison of unseeded and seeded aggregation kinetics suggests that these compounds preferentially target early-stage aggregation.
Weaknesses:
The authors state their interest is in finding compounds that target monomeric states of tau, but their only detection method is late-stage fibril formation. In this respect, they have not really defined a mechanism of action. They state their plan to use hydrogen-exchange mass spectrometry, but there are other techniques, such as single-molecule FRET and measurement of intramolecular reconfiguration. Additionally, there is information that can be gleaned from detailed kinetic modeling of the ThT kinetics to include monomer dynamics, formation of oligomers, and secondary nucleation of fibrils.
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Reviewer #2 (Public Review):
Summary:
James et al, in this study, build on their previous work investigating tau as a drug target. The authors identify tryptanthrin (TA) and its analogs as powerful inhibitors of tau4RD aggregation, even at low concentrations (nanomolar range). Interestingly, these analogs specifically target the initial stages of aggregation, where tau self-association first begins. This targeted approach effectively explains why such small amounts of tryptanthrin analogs are sufficient for inhibition. The study further shows that slight modifications to the structure of these molecules can significantly impact their effectiveness.
Strengths:
The experiments are well-designed and executed. The reviewer, in particular, appreciates the authors for the simple yet intelligent study design to understand the mechanism of …
Reviewer #2 (Public Review):
Summary:
James et al, in this study, build on their previous work investigating tau as a drug target. The authors identify tryptanthrin (TA) and its analogs as powerful inhibitors of tau4RD aggregation, even at low concentrations (nanomolar range). Interestingly, these analogs specifically target the initial stages of aggregation, where tau self-association first begins. This targeted approach effectively explains why such small amounts of tryptanthrin analogs are sufficient for inhibition. The study further shows that slight modifications to the structure of these molecules can significantly impact their effectiveness.
Strengths:
The experiments are well-designed and executed. The reviewer, in particular, appreciates the authors for the simple yet intelligent study design to understand the mechanism of aggregation inhibition by TA analogs.
Weaknesses:
Certain areas in the manuscript need clarifications, revisions, or additional supporting studies to strengthen the outcomes. For example, the authors mostly apply a single approach to assess tau aggregation or aggregation inhibition. Using additional techniques as suggested below will be helpful.
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