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Aptamers inhibiting the protein CD73 as possible antitumoral agents

Grant number: 13/02293-5
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): July 01, 2013
Effective date (End): June 30, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Alexander Henning Ulrich
Grantee:Arquimedes Cheffer
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:12/50880-4 - Stem cells: from basic studies of kinin and purinergic receptor roles towards therapeutical applications, AP.TEM
Associated scholarship(s):16/24629-3 - Role of t-SNARE1 in exocytosis of dopaminergic neurons derived from SH-SY5Y cells, BE.EP.PD

Abstract

The metabolism of ATP into its metabolites ADP, AMP, and adenosine, and consequently, the regulation of purinergic signaling, is a tightly regulated process by a family of cell surface-located ecto-nucleotidases, including nucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5'-nucleotidase (CD73). AMP is generated by the stepwise catabolism of ATP via the intermediate ADP in two reactions predominantly carried out by CD39 (NTPDase-1), whereas CD73 is required for the conversion of AMP to adenosine. Adenosine, in turn, is able to activate receptors expressed in membranes of immune system cells, playing a profound immunosuppressive effect. This draws attention to CD73 as a potential therapeutic target against cancer, in which immune system suppression is crucial for the initiation of malignant neoplasms and the progression of established tumors. Indeed, recent evidence suggests that CD73 inhibition reduces tumorigenesis and metastasis, as well as enhances the efficacy of conventional therapies. However, we still have available only very few CD73 inhibitors for pre-clinical trials. Here we propose to develop aptamers targeting CD73, by using the SELEX (Systematic Evolution of Ligands by Exponential Enrichment) technique. These oligonucleotides developed by an in vitro selection protocol show affinity and specificity comparable to those obtained with monoclonal antibodies, are easily produced and optimized and lack of immunogenicity, representing a promising alternative for the use of small molecules and antibodies.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CHEFFER, A.; CASTILLO, A. R. G.; CORREA-VELLOSO, J.; GONCALVES, M. C. B.; NAALDIJK, Y.; NASCIMENTO, I. C.; BURNSTOCK, G.; ULRICH, H. Purinergic system in psychiatric diseases. MOLECULAR PSYCHIATRY, v. 23, n. 1, p. 94-106, JAN 2018. Web of Science Citations: 21.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.