Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

Glaucio Monteiro Ferreira; Thales Kronenberger; Vinicius Gonçalves Maltarollo; Antti Poso; Fernando de Moura Gatti; Vitor Medeiros Almeida; Sandro Roberto Marana; Carla Duque Lopes; Daiane Yukie Tezuka; Sérgio de Albuquerque; Flavio da Silva Emery; Gustavo Henrique Goulart Trossini

doi:10.3390/ph16030428

Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design

Pharmaceuticals (Basel). 2023 Mar 10;16(3):428. doi: 10.3390/ph16030428.

Authors

Affiliations

¹ Department of Pharmacy, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 13, São Paulo 05508-000, SP, Brazil.
² Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, Av Prof Lineu Prestes 580, Building. 17, São Paulo 05508-000, SP, Brazil.
³ Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany.
⁴ School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
⁵ Department of Pharmaceutical Products, Faculty of Pharmacy, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte 31270-901, MG, Brazil.
⁶ Department of Biochemistry, Institute of Chemistry, University of São Paulo, Av Prof Lineu Prestes 748, Building 12, São Paulo 05508-000, SP, Brazil.
⁷ Department of Clinical Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil.
⁸ Department of Pharmaceutical Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, Ribeirão Preto 14040-903, SP, Brazil.

Abstract

Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD⁺-dependent class III histone deacetylase, to interfere with the parasites' cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC₅₀ = 40 μM) was chosen as a potential lead compound.

Keywords: Sirtuin 2; Trypanosoma cruzi; anti-infectives; computer-aided drug discovery.

Grants and funding

This research was funded by [Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)] grant number [436791/2018-8, 310232/2017-1, 2019/06172-4, 2017/25543-8 and 2016/22365-9].