Identification of an ex vivo inhibitor of the schizophrenia biomarker Ndel1 by high throughput screening

Author(s)

Nani, Joao V. ; Coelho, Camila ; Oyadomari, William Y. ; Santiago, Thays Calista ; Machado, Marcelo Marcondes ; Christoff, Raissa R. ; Garcez, Patricia P. ; Oliveira, Vitor ; Wurtele, Martin ; Hayashi, Mirian A. F.

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 217, p. 11-pg., 2023-10-14.

Abstract

Ndel1 oligopeptidase activity shows promise as a potential biomarker for diagnosing schizophrenia (SCZ) and monitoring early-stage pharmacotherapy. Ndel1 plays a pivotal role in critical aspects of brain development, such as neurite outgrowth, neuronal migration, and embryonic brain formation, making it particularly relevant to neurodevelopmental disorders like SCZ. Currently, the most specific inhibitor for Ndel1 is the polyclonal anti-Ndel1 antibody (NOAb), known for its high specificity and efficient anti-catalytic activity. NOAb has been vital in measuring Ndel1 activity in humans and animal models, enabling the prediction of pharmacological responses to antipsychotics in studies with patients and animals. To advance our understanding of in vivo Ndel1 function and develop drugs for mental disorders, identifying small chemical compounds capable of specifically inhibiting Ndel1 oligopeptidase is crucial, including within living cells. Due to challenges in obtaining Ndel1 ' s three-dimensional structure and its promiscuous substrate recognition, we conducted a high-throughput screening (HTS) of 2,400 small molecules. Nine compounds with IC50-values ranging from 7 to 56 mu M were identified as potent Ndel1 inhibitors. Notably, one compound showed similar efficacy to NOAb and inhibited Ndel1 within living cells, although its in vivo use may pose toxicity concerns. Despite this, all identified compounds hold promise as candidates for further refinement through rational drug design, aiming to enhance their inhibitory efficacy, specificity, stability, and biodistribution. Our ultimate goal is to develop druggable Ndel1 inhibitors that can improve the treatment and support the diagnosis of psychiatric disorders like SCZ. (AU)

• FAPESP's process: 19/09207-3 - Study of molecular and cellular mechanisms in mental disorders
• Grantee: João Victor Silva Nani
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 23/07904-4 - Study of molecular and cellular mechanisms of mental disorders: clinical studies and animal models
• Grantee: William Yoshio Agliardi Oyadomari
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/01107-7 - Study to optimize the use of crotamine as a theranostic in the therapy of human diseases: cancer, metabolic syndrome and renal dysfunction
• Grantee: Mirian Akemi Furuie Hayashi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/00527-8 - Enzymatic activity of oligopeptidases Ndel1 and/or ACE in plasma or blood serum of patients with Depression
• Grantee: Larissa Ribino Parra
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/02413-1 - Validation of crotamine as a biomarker and evaluation of its potential use in the therapy of human diseases
• Grantee: Mirian Akemi Furuie Hayashi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/08287-3 - Effect of crotamine on glucose uptake by brown adipose tissue: evaluation in an experimental model with 18FDG PET
• Grantee: Marcelo Tatit Sapienza
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/03297-3 - Exploring the molecular and cellular mechanism(s) underlying neurodevelopmental disorders: investigating the role(s) of Nuclear Distribution Element like-1 (Ndel1)
• Grantee: João Victor Silva Nani
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 19/13112-8 - Study of molecular and cellular mechanisms involved in mental disorders: clinical and animal models analysis
• Grantee: Mirian Akemi Furuie Hayashi
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/50891-1 - INCT 2014: Translational Medicine
• Grantee: Jaime Eduardo Cecilio Hallak
• Support Opportunities: Research Projects - Thematic Grants