Parasitic Sirtuin 2 As an Opportunity in Drug Discovery

Abstract

Infections caused by protozoans remain a public health issue, especially in tropical countries. Serious adverse events, lack of efficacy at the different stages of the infection and routes of administration that have a negative impact on treatment adherence are some of the problems with currently available therapy against these diseases. Here we describe an epigenetic target, sirtuin 2 and its related proteins, that is promising given the results in phenotypic assays and in vivo models against Sir2 of Plasmodium falciparum, Leishmania donovani, Leishmania infantum, Schistosoma mansoni, Trypanosoma brucei and Trypanosoma cruzi parasites. The results we present highlight how this target can be extensively explored and how its inhibitors might be employed in the clinic.

Chromosome‐level genome assembly defines female‐biased genes associated with sex determination and differentiation in the human blood fluke Schistosoma japonicum

“…Sir2 is a member of the class of histone deacetylases, which coordinate the DNA transcription by deacetylation of histones (Strahl & Allis, 2000). Sir2s are widely present in all phyla, and they play different roles depending on the organism (Gomes et al, 2021; Religa & Waters, 2012). In S. mansoni , Sm Sir2 was first reported by Lancelot et al (2013).…”

Triagem biológica de inibidores de sirtuína 2 (>i<Tc>/i<Sir2rp1) candidatos a antichagásicos

“…A SIRT2, apresenta apenas 29% de identidade com a enzima parasitária (TcSir2rp1), já em relação a SIRT3, esta apresenta 24% de identidade com a TcSir2rp1. Desta maneira, visto a baixa similaridade/ identidade acredita-se que este alvo seja adequado na busca de compostos inibitórios como promissores anti-T.cruzi (SOARES et al, 2012;HAILU et al, 2017, BASTOS et al, 2020GOMES et al, 2021).…”

“…Estas modificações são realizadas por duas famílias de enzimas: as lisinas acetiltransferases (KATs) e as lisinas deacetilases (KDACs). As KATs + , ocorrendo a transferência do grupo acetil de lisina para ADP-ribose, resultando na lisina deacetilada, nicotinamida e o 2'-e 3'-O-acetil-ADP-ribose (Figura 4)(GASPAR et al, 2018;ZHOU et al, 2018;GOMES et al, 2021).Figura 4: Esquema do mecanismo da deacetilação da sirtuína 2. Fonte: Adaptado de GOMES et al, 2021.As Sir2 estão presentes em todos os reinos da vida, desde bactérias até seres humanos e demonstram ser pró-sobrevivência em parasitas(LI et al, 2015;HU;ZHENG, 2018;MONALDI et al, 2019).…”