Researchers from the universities of São Paulo (USP) and California in San Diego, in the United States, will be able to reproduce in the laboratory the performance of an enzyme that is directly related to various diseases.
A compreensão sobre o funcionamiento das phosphatase enzymes which are involved in a series of biological processes, can open doors for the investigation of drugs that have efficacy on it.
The results of the study were published not Journal of Biological Chemistry.
complex task
A protein of this class, known as PTPN2 (acronym in English for non-receptor protein tyrosine phosphatase type 2), is highly expressed in T cells (lymphocytes) of the immune system (by this, it is also known as protein tyrosine phosphatase of T cells or, simply, TCPTP) and its deficiency stimulates inflammatory responses as it occurs in cases of type 1 diabetes, rheumatoid arthritis, osteoarthritis, lupus and certain types of cancers.
Understanding its molecular mechanism in the laboratory, however, was a complex task, since its behavior was different from that of an organism.
The investigation has started with an extensive search in the scientific literature so that the authors can think of strategies to be applied to us. in vitro, those carried out in the laboratory, in order to simulate the intracellular environment. This was achieved after countless experimental trials without success.
“We discovered that, inside different human cells, PTPN2 naturally aggregates, reducing its enzymatic action and, therefore, in the laboratory, we launched more drugs called crowding agents, which promote this aggregation without affecting the activity of the enzyme”, explains Fábio Luis Forti, professor of the Department of Biochemistry of the Institute of Chemistry of USP and co-author of the study.
The researchers believe that this factor can explain why an enzyme that is so relevant is still poorly understood at the molecular level. live, despite much research. From now on, accredited, new studies must emerge. “We were able to reproduce the same results of the PTPN2 activity, even in some that are directly involved in immunological responses.”
The enzyme acts directly, for example, on the JAK-STAT signaling pathway, the main one involved in gene expression aimed at immune responses. “Any chemical, physical or biological mechanism that triggers an immune response in our cells is normally mediated by this way”, explains Forti.
The study had the support of the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
Differentiated medicines
Unlike the many enzymes involved in cancers and other pathologies, which are very present or have mutations that make them very active, requiring the action of drugs that block their functioning (most of the two medicines have no sense), the PTPN2 gene presents polymorphisms (alternative forms of the gene) that lead to the loss of their protein function – and this is linked to the fact that they group together naturally. Or say, it is its enzymatic deficiency or inefficiency that causes the patient to have exacerbated inflammation and autoimmune reaction.
“Knowing this, we can search for better existing oral, nasal or injectable drugs that can act directly on the activation of this enzyme in cases where it is naturally inactive, which is what happens in lupus, in rheumatoid arthritis, or in type 1 diabetes. , in certain lymphomas, not breast cancer and not glioblastoma [tumor maligno que afeta o cérebro e a coluna]”, affirms Forti.
“Also, our work opens an interesting avenue of exploration for the development of new drugs that have these functions, which is what we intend to do in a sequence by means of libraries of synthetic and/or natural compounds by appropriate technologies based on the tests that we develop with this study”, he adds.
To contribute to this mission, the group of researchers from the United States maintains collaborations with biotechnology startups and other pharmaceutical companies that are attentive to the latest discoveries related to phosphatases, which are still some poorly explored pharmacologicals.