Mouse Anti-Human CFTR Hybridoma [mAb 35-3]

Background: Cystic fibrosis related diabetes (CFRD) is the most common co-morbidity associated with cystic fibrosis (CF). Individuals with CF demonstrate airway and systemic oxidation compared to people without CF. Furthermore, systemic oxidation precipitated by hyperglycemia in non-CF diabetes has been shown to lead to enhanced inflammation. We hypothesized that the presence of both CF and diabetes in an individual would result in hyperglycemia-induced redox imbalance to an oxidative state. This in turn would result in enhanced production of pro-inflammatory cytokines. Methods: Systemic redox balance and pro-inflammatory cytokines were measured before and following a standard oral glucose tolerance test in healthy controls (HC) and in CF individuals with a spectrum of glucose homeostasis (i.e. normal glucose tolerant - NGT, prediabetes or frank CFRD). Results: There were no significant differences between groups in terms of basal or glucose-induced levels of inflammatory markers. However, baseline systemic redox potential was significantly more oxidized in CF subjects with prediabetes and CFRD compared to both CF with NGT and HC. Systemic oxidation was significantly worsened, and to a profound degree, two hours following ingestion of glucose in all CF groups (NGT, prediabetes, and CFRD). The level of redox imbalance at the two hour point was the same in all three CF groups and was not associated with the degree of hyperglycemia. There was a significant correlation between worse systemic oxidation and reduced insulin secretion. Conclusions: This supports a newly identified abnormality of metabolism in CF - glucose induced redox imbalance to the oxidative state. (C) 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. Different mutations involving the cystic fibrosis transmembrane regulator protein (CFTR) gene, which encodes the CFTR channel, are involved in CF. A number of life-prolonging therapies have been conceived and deeply investigated to combat this disease. Among them, the administration of the so-called CFTR modulators, such as correctors and potentiators, have led to quite beneficial effects. Recently, based on QSAR (quantitative structure activity relationship) studies, we reported the rational design and synthesis of compound 2, an aminoarylthiazole-VX-809 hybrid derivative exhibiting promising F508del-CFTR corrector ability. Herein, we explored the docking mode of the prototype VX-809 as well as of the aforementioned correctors in order to derive useful guidelines for the rational design of further analogues. In addition, we refined our previous QSAR analysis taking into account our first series of in-house hybrids. This allowed us to optimize the QSAR model based on the chemical structure and the potency profile of hybrids as F508del-CFTR correctors, identifying novel molecular descriptors explaining the SAR of the dataset. This study is expected to speed up the discovery process of novel potent CFTR modulators.