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THE SEARCH FOR NEW AGONISTS TO P2X7R FOR CLINICAL USE: TUBERCULOSIS AS A POSSIBLE TARGET
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Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Comunicação Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.
Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Comunicação Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.
Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ). Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunologia Clínica. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Comunicação Celular. Rio de Janeiro, RJ, Brasil.
Abstract
Treatment for tuberculosis is effective with the use of proper antibiotics, but the number of
drug-resistant cases is increasing. Drug resistance occurred in 650,000 cases of the 20 million
patients in treatment worldwide in 2011, which demonstrates the necessity of finding new
therapeutic approaches. In this context, the search for new medicines and immunomodulators
could help reduce the prevalence and incidence of multi-drug-resistant tuberculosis cases.
Thus several preclinical studies demonstrate the involvement of the P2X7 receptor (P2X7R)
in the control of Mycobacterium tuberculosis (MTB) infection. Adenosine triphosphate (ATP), a
natural agonist for P2X7R, promotes MTB death and the induction of apoptosis in monocytes
and macrophages infected with MTB via activation of P2X7R by extracellular ATP. In addition,
P2X7R activation in the presence of ATP increases the expression of major histocompatibility
complex (MHC) class II by macrophages infected with Mycobacterium bovis (BCG) or MTB,
which contributes to the generation of the antimicrobial immune response via T cells.
Nevertheless, one idea that seems overlooked by the “purinergic community” is the use of the
high-conductance channel associated with P2X7R to increase the passage of hydrophilic drugs
to the cytoplasm of cells that express the P2X7 pore, a potential method for a drug delivery
system. In this work, we propose the use of P2X7 agonists in conjunction with low molecular
weight anti-tuberculosis medicines for the treatment of multi-drug-resistant tuberculosis.
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