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Hexahydropyrrolo[2,3-b]indole Compounds as Potential Therapeutics for Alzheimer's Disease.
Doens, Deborah; Valdés-Tresanco, Mario E; Vasquez, Velmarini; Carreira, Maria Beatriz; De La Guardia, Yila; Stephens, David E; Nguyen, Viet D; Nguyen, Vu T; Gu, Jianhua; Hegde, Muralidhar L; Larionov, Oleg V; Valiente, Pedro A; Lleonart, Ricardo; Fernández, Patricia L.
Afiliação
  • Doens D; Centro de Biología Celular y Molecular de Enfermedades , Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge Edif #208 , Panama 0843-01103 , Panama.
  • Valdés-Tresanco ME; Department of Biotechnology , Acharya Nagarjuna University , Nagarjuna Nagar , Guntur , Andhra Pradesh 522510 , India.
  • Vasquez V; Centro de Estudios de Proteínas, Facultad de Biología , Universidad de La Habana , Calle 25 No. 455 , Vedado, La Habana , Cuba.
  • Carreira MB; Department of Biotechnology , Acharya Nagarjuna University , Nagarjuna Nagar , Guntur , Andhra Pradesh 522510 , India.
  • De La Guardia Y; Department of Radiation Oncology , Houston Methodist Research Institute , Houston , Texas 77030 , United States.
  • Stephens DE; Centro de Neurociencias , INDICASAT-AIP , City of Knowledge Edif #208 , Panama , 0843-01103 , Panama.
  • Nguyen VD; Centro de Biología Celular y Molecular de Enfermedades , Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge Edif #208 , Panama 0843-01103 , Panama.
  • Nguyen VT; Department of Chemistry , University of Texas at San Antonio , One UTSA Circle , San Antonio , Texas 78249 , United States.
  • Gu J; Department of Chemistry , University of Texas at San Antonio , One UTSA Circle , San Antonio , Texas 78249 , United States.
  • Hegde ML; Department of Chemistry , University of Texas at San Antonio , One UTSA Circle , San Antonio , Texas 78249 , United States.
  • Larionov OV; AFM SEM Core , Houston Methodist Research Institute , Houston , Texas 77030 , United States.
  • Valiente PA; Department of Radiation Oncology , Houston Methodist Research Institute , Houston , Texas 77030 , United States.
  • Lleonart R; Department of Chemistry , University of Texas at San Antonio , One UTSA Circle , San Antonio , Texas 78249 , United States.
  • Fernández PL; Centro de Estudios de Proteínas, Facultad de Biología , Universidad de La Habana , Calle 25 No. 455 , Vedado, La Habana , Cuba.
ACS Chem Neurosci ; 10(10): 4250-4263, 2019 10 16.
Article em En | MEDLINE | ID: mdl-31545596
Alzheimer's disease (AD) is the most common form of dementia among the elderly and has become a leading public health concern worldwide. It represents a huge economic and psychological burden to caregivers and families. The presence of extracellular amyloid beta (Aß) plaques is one of the hallmarks of this neurodegenerative disorder. Amyloid plaques are comprised of aggregates of Aß peptides, mainly Aß42, originated by the cleavage of the amyloid precursor protein (APP). Aß is a crucial target for the treatment of AD, but to date, no effective treatment for the clearance of Aß has been found. We have identified four new hexahydropyrroloindoles (HPI) synthetic compounds that are able to inhibit the aggregation of Aß42 and/or disaggregate the fibril. Docking experiments suggest that the nonpolar component of the interaction of compounds with Aß42 contributes favorably to the binding free energy of each complex. Molecular dynamics simulations suggested fibril disaggregating activity of compounds 1 via interaction with hydrophobic moieties of the fibril. Consistently, compounds 1 and 2 were able to mitigate Aß42 fibrils induced death in rat pheochromocytoma cells (PC 12). One of the compounds reduces the formation of Aß aggregates in vivo and the paralysis associated with Aß toxicity in Caenorhabditis elegans. Our study thus augments efforts for the identification and characterization of new agents that may help stop or delay the progression of AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Pirróis / Peptídeos beta-Amiloides / Doença de Alzheimer / Agregação Patológica de Proteínas / Agregados Proteicos / Indóis Limite: Animals Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Panamá País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Pirróis / Peptídeos beta-Amiloides / Doença de Alzheimer / Agregação Patológica de Proteínas / Agregados Proteicos / Indóis Limite: Animals Idioma: En Revista: ACS Chem Neurosci Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Panamá País de publicação: Estados Unidos