Synthesis and characterization of inhibitors for human and citrus deadenylase CAF1 (CNOT7)

• Grant number: 17/07641-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2017
• End date: December 31, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Celso Eduardo Benedetti
• Grantee: Carolina Terassi
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated research grant: 11/20468-1 - Molecular mechanisms involved in pathogen adaptation and virulence, host resistance and symptom development in citrus-bacteria interactions, AP.TEM

Abstract

CAF1 (CCR4-NOT-associated factor), also known as CNOT7, is a component of the eukaryotic CCR4-NOT complex that regulates not only the synthesis but also the destruction of mRNAs in the cell. CAF1 is conserved from yeast to man and it presents deadenylase activity upon the poli(A) tail of mRNAs. Thus, CAF1 plays an essential role in gene regulation through an mRNA decay mechanism. In a previous work, we have identified the CsCAF1 of Citrus sinensis as a plant factor contributing to the defense response against Xanthomonas citri, the causal agent of citrus canker disease. With the aim of studying the CsCAF1 role in the defense response against X. citri, quinazoline-based inhibitors of CsCAF1 were synthetized and tested. Some of them inhibited the CsCAF1 deadenylase activity in vitro and altered the development of the canker lesions. These results and the fact that CAF1 inhibitors with desired selectivity/specificity and potency are not commercially available or have been reported for members of the CAF1 family prompt us to try to synthesize new inhibitors for CAF1 proteins, particularly for human CAF1. Thus, the main objective of this proposal is to obtain inhibitors for human CAF1, which has been recently shown to promote metastases of certain tumors. Thus, despite their potential therapeutic use, such inhibitors could also be exploited as probes in biochemical and physiological studies to modulate the deadenylase activity of CAF1 proteins in cell culture, animals and plants. (AU)