2. Academic Validation
  3. Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease

Design, Synthesis, and Evaluation of a Novel Conjugate Molecule with Dopaminergic and Neuroprotective Activities for Parkinson's Disease

  • ACS Chem Neurosci. 2024 Jul 11. doi: 10.1021/acschemneuro.4c00169.
Diego Ploper 1,  Agustín O Pernicone 2 3,  Rodrigo H Tomas-Grau 1,  Verónica E Manzano 2 3,  Sergio B Socías 1,  María Del Milagro Teran 1,  Valentina Budeguer Isa 1,  Bernardo Sosa-Padilla 4,  Florencia González-Lizárraga 1,  César L Avila 1,  María Laura Guayán 1,  Silvina Chaves 1,  Hernán Cruz 5,  Esteban Vera Pingitore 1,  Oscar Varela 2 3,  Rosana Chehín 1
Affiliations

Affiliations

  • 1 Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET), Universidad Nacional de Tucumán (UNT), Ministerio de Salud Pública de Tucumán - SIPROSA, Pasaje Dorrego 1080, 4000 San Miguel de Tucumán, Tucumán, Argentina.
  • 2 Facultad de Ciencias Exactas y Naturales, Departamento de Química Orgánica, Universidad de Buenos Aires, Pabellón 2, C1428EHA Buenos Aires, Argentina.
  • 3 Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Investigación en Hidratos de Carbono (CIHIDECAR), Ciudad Universitaria, C1428EHA Buenos Aires, Argentina.
  • 4 Instituto de Química del Noroeste Argentino (INQUINOA) (CONICET), Universidad Nacional de Tucumán (UNT), Ayacucho 471, 4000 San Miguel de Tucumán, Tucumán, Argentina.
  • 5 Instituto de Química Física, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, San Lorenzo 456, 4000 San Miguel de Tucumán, Tucumán, Argentina.
PMID: 38991155 DOI: 10.1021/acschemneuro.4c00169
Abstract

The escalating prevalence of Parkinson's disease (PD) underscores the need for innovative therapeutic interventions since current palliative measures, including the standard l-Dopa formulations, face challenges of tolerance and side effects while failing to address the underlying neurodegenerative processes. Here, we introduce DAD9, a novel conjugate molecule that aims to combine symptomatic relief with disease-modifying strategies for PD. Crafted through knowledge-guided chemistry, the molecule combines a nonantibiotic doxycycline derivative with dopamine, preserving neuroprotective attributes while maintaining dopaminergic agonism. This compound exhibited no off-target effects on PD-relevant cell functions and sustained antioxidant and anti-inflammatory properties of the Tetracycline precursor. Furthermore, it effectively interfered with the formation and seeding of toxic α-synuclein aggregates without producing detrimental oxidative species. In addition, DAD9 was able to activate dopamine receptors, and docking simulations shed LIGHT onto the molecular details of this interaction. These findings position DAD9 as a potential neuroprotective dopaminergic agonist, promising advancements in PD therapeutics.

Keywords

DAD9; Parkinson’s disease; α-synuclein.

Figures
Products