Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1

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dc.contributorLab. Fisiopatologiapt_BR
dc.contributor.authorBoldin, Renatapt_BR
dc.contributor.authorZychar, Bianca Cestaript_BR
dc.contributor.authorGonçalves, Luis Roberto de Camargopt_BR
dc.contributor.authorSciani, Juliana Mozerpt_BR
dc.identifier.citationBoldin R, Zychar BC, Gonçalves LRC, Sciani JM. Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1. Front Pharmacol. 2023 Jun; 14:1184006. doi:10.3389/fphar.2023.1184006.pt_BR
dc.description.abstractIntroduction: Alzheimer’s disease (AD) is the main type of dementia, caused by the accumulation of amyloid plaques, formed by amyloid peptides after being processed from amyloid precursor protein (APP) by γ- and ß-secretases (BACE-1). Although amyloid peptides have been well established for AD, they have been found in other neurodegenerative diseases, such as Parkinson’s disease, Lewy body dementia, and amyotrophic lateral sclerosis. Inhibitors of BACE-1 have been searched and developed, but clinical trials failed due to lack of efficacy or toxicity. Nevertheless, it is still considered a good therapeutic target, as it was proven to remove amyloid peptides and improve memory. Methods: In this work, we designed a peptide based on a sequence obtained from the marine fish Merluccius productus and evaluated it by molecular docking to verify its binding to BACE-1, which was tested experimentally by enzymatic kinetics and cell culture assays. The peptide was injected in healthy mice to study its pharmacokinetics and toxicity. Results: We could obtain a new sequence in which the first N-terminal amino acids and the last one bound to the catalytic site of BACE-1 and showed high stability and hydrophobicity. The synthetic peptide showed a competitive inhibition of BACE-1 and Ki = 94 nM, and when injected in differentiated neurons, it could reduce Aβ42o production. In plasma, its half-life is ∼1 h, clearance is 0.0015 μg/L/h, and Vss is 0.0015 μg/L/h. The peptide was found in the spleen and liver 30 min after injection and reduced its level after that, when it was quantified in the kidneys, indicating its fast distribution and urinary excretion. Interestingly, the peptide was found in the brain 2 h after its administration. Histological analysis showed no morphological alteration in any organ, as well as the absence of inflammatory cells, indicating a lack of toxicity. Discussion: We obtained a new BACE-1 inhibitor peptide with fast distribution to the tissues, without accumulation in any organ, but found in the brain, with the possibility to reach its molecular target, BACE-1, contributing to the reduction in the amyloid peptide, which causes amyloid-linked neurodegenerative diseases.pt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.relation.ispartofFrontiers in Pharmacologypt_BR
dc.rightsOpen accesspt_BR
dc.titleDesign, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1pt_BR
dc.rights.licenseCC BYpt_BR
dc.contributor.external(UNIFAG) Unidade Integrada de Farmacologia e Gastroenterologiapt_BR
dc.contributor.external(USF) Universidade São Franciscopt_BR
dc.subject.keywordcompetitive inhibitorpt_BR
dc.subject.keywordin silico designpt_BR
dc.relation.ispartofabbreviatedFront Pharmacolpt_BR
dc.identifier.citationabntv. 14, 1184006, jun. 2023pt_BR
dc.identifier.citationvancouver2023 Jun; 14:1184006pt_BR
dc.contributor.butantanZychar, Bianca Cestari|:Pesquisador|:Lab. Fisiopatologia|:pt_BR
dc.contributor.butantanGonçalves, Luis Roberto de Camargo|:Pesquisador|:Lab. Fisiopatologia|:Autor de correspondência|:pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2019/19929-6pt_BR
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