Background: Amyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer's disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease. Therefore, to build on this important efficacy attribute and to further improve its pharmaceutical properties, we have developed a prodrug of tramiprosate ALZ-801 that is in advanced stages of clinical development. To elucidate how tramiprosate works, we investigated its molecular mechanism of action (MOA) and the translation to observed clinical outcomes.
Objective: The two main objectives of this research were to (1) elucidate and characterize the MOA of tramiprosate via an integrated application of three independent molecular methodologies and (2) present an integrated translational analysis that links the MOA, conformation of the target, stoichiometry, and pharmacokinetic dose exposure to the observed clinical outcome in APOE4/4 homozygote subjects.
Method: We used three molecular analytical methods-ion mobility spectrometry-mass spectrometry (IMS-MS), nuclear magnetic resonance (NMR), and molecular dynamics-to characterize the concentration-related interactions of tramiprosate versus Aβ42 monomers and the resultant conformational alterations affecting aggregation into oligomers. The molecular stoichiometry of the tramiprosate versus Aβ42 interaction was further analyzed in the context of clinical pharmacokinetic dose exposure and central nervous system Aβ42 levels (i.e., pharmacokinetic-pharmacodynamic translation in humans).
Results: We observed a multi-ligand interaction of tramiprosate with monomeric Aβ42, which differs from the traditional 1:1 binding. This resulted in the stabilization of Aβ42 monomers and inhibition of oligomer formation and elongation, as demonstrated by IMS-MS and molecular dynamics. Using NMR spectroscopy and molecular dynamics, we also showed that tramiprosate bound to Lys16, Lys28, and Asp23, the key amino acid side chains of Aβ42 that are responsible for both conformational seed formation and neuronal toxicity. The projected molar excess of tramiprosate versus Aβ42 in humans using the dose effective in patients with AD aligned with the molecular stoichiometry of the interaction, providing a clear clinical translation of the MOA. A consistent alignment of these preclinical-to-clinical elements describes a unique example of translational medicine and supports the efficacy seen in symptomatic patients with AD. This unique "enveloping mechanism" of tramiprosate also provides a potential basis for tramiprosate dose selection for patients with homozygous AD at earlier stages of disease.
Conclusion: We have identified the molecular mechanism that may account for the observed clinical efficacy of tramiprosate in patients with APOE4/4 homozygous AD. In addition, the integrated application of the molecular methodologies (i.e., IMS-MS, NMR, and thermodynamics analysis) indicates that it is feasible to modulate and control the Aβ42 conformational dynamics landscape by a small molecule, resulting in a favorable Aβ42 conformational change that leads to a clinically relevant amyloid anti-aggregation effect and inhibition of oligomer formation. This novel enveloping MOA of tramiprosate has potential utility in the development of disease-modifying therapies for AD and other neurodegenerative diseases caused by misfolded proteins.
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http://dx.doi.org/10.1007/s40263-017-0434-z | DOI Listing |
Int J Biol Macromol
January 2025
College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, Republic of Korea. Electronic address:
Alzheimer's disease (AD) is characterized as a neurodegenerative disorder that is caused by plaque formation by accumulating β-amyloid (Aβ), leading to neurocognitive function and impaired mental development. Thus, targeting Aβ represents a promising target for the development of therapeutics in AD management. Several functionalized sulfonic acid molecules have been reported, including tramiprosate prodrug, which is currently in clinical trial III and exhibits a good response in mild to moderate AD patients.
View Article and Find Full Text PDFMolecules
August 2024
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy.
-Homocysteine, formed from S-adenosyl methionine following demethylation and adenosine release, accumulates when the methionine recycling pathway and other pathways become impaired, thus leading to hyperhomocysteinemia, a biomarker in cardiovascular diseases, neurological/psychiatric disorders, and cancer. The partial oxidation of the -homocysteine thiol group and its decarboxylation on C-alpha lead to the formation of -homocysteinesulfinic acid (-HCSA) and homohypotaurine (HHT), respectively. Both compounds are not readily available from commercial suppliers, which hinders the investigation of their biological activities.
View Article and Find Full Text PDFMolecules
July 2024
Institute of Physical Chemistry 'Acad. R. Kaischew', Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
The kinetics of amyloid aggregation was studied indirectly by monitoring the changes in the polydispersity of mixed dispersion of amyloid β peptide (1-40) and composite liposomes. The liposomes were prepared from the 1,2-dioleoyl-sn-glicero-3-phoshocholine (DOPC) phospholipid and stabilised by the electrostatic adsorption of κ-carrageenan. The produced homotaurine-loaded and unloaded liposomes had a highly negative electrokinetic potential and remarkable stability in phosphate buffer (pH 4 and 7.
View Article and Find Full Text PDFJACS Au
June 2024
Loschmidt Laboratories, Department of Experimental Biology and RECETOX, Faculty of Science, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic.
Computational study of the effect of drug candidates on intrinsically disordered biomolecules is challenging due to their vast and complex conformational space. Here, we developed a comparative Markov state analysis (CoVAMPnet) framework to quantify changes in the conformational distribution and dynamics of a disordered biomolecule in the presence and absence of small organic drug candidate molecules. First, molecular dynamics trajectories are generated using enhanced sampling, in the presence and absence of small molecule drug candidates, and ensembles of soft Markov state models (MSMs) are learned for each system using unsupervised machine learning.
View Article and Find Full Text PDFExpert Opin Pharmacother
May 2024
Alzheimer's Disease Care, Research and Education (AD-CARE), Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD.
Areas Covered: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.
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