Faculty Opinions recommendation of The ankyrin repeats of TRPV1 bind multiple ligands and modulate channel sensitivity.

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

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Receptor crosstalk improves concentration sensing of multiple ligands

Physical Review E ◽

10.1103/physreve.99.022423 ◽

2019 ◽

Vol 99 (2) ◽

Cited By ~ 13

Author(s):

Martín Carballo-Pacheco ◽

Jonathan Desponds ◽

Tatyana Gavrilchenko ◽

Andreas Mayer ◽

Roshan Prizak ◽

...

Keyword(s):

Receptor Crosstalk ◽

Multiple Ligands

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Solution Structure of the Human Oncogenic Protein Gankyrin Containing Seven Ankyrin Repeats and Analysis of Its Structure−Function Relationship†,‡

Biochemistry ◽

10.1021/bi049116o ◽

2004 ◽

Vol 43 (38) ◽

pp. 12152-12161 ◽

Cited By ~ 25

Author(s):

Chunhua Yuan ◽

Junan Li ◽

Anjali Mahajan ◽

Ming Jye Poi ◽

In-Ja L. Byeon ◽

...

Keyword(s):

Structure Function ◽

Solution Structure ◽

Ankyrin Repeats ◽

Structure Function Relationship ◽

Function Relationship ◽

Oncogenic Protein

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The membrane-binding domain of ankyrin contains four independently folded subdomains, each comprised of six ankyrin repeats.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)41584-0 ◽

1993 ◽

Vol 268 (30) ◽

pp. 22703-22709

Author(s):

P Michaely ◽

V Bennett

Keyword(s):

Membrane Binding ◽

Binding Domain ◽

Ankyrin Repeats

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Apoptotic cell and phagocyte interplay: recognition and consequences in different cell systems

Anais da Academia Brasileira de Ciências ◽

10.1590/s0001-37652004000100009 ◽

2004 ◽

Vol 76 (1) ◽

pp. 93-115 ◽

Cited By ~ 24

Author(s):

Maria Elisabete C. Moreira ◽

Marcello A. Barcinski

Keyword(s):

Cell Death ◽

Cell Surface ◽

Molecular Interactions ◽

Apoptotic Cell ◽

Cell Recognition ◽

Cell Systems ◽

Cellular Models ◽

Pathological Conditions ◽

Multiple Ligands ◽

Multiple Receptor

Cell death by apoptosis is characterized by specific biochemical changes, including the exposure of multiple ligands, expected to tag the dying cell for prompt recognition by phagocytes. In non-pathological conditions, an efficient clearance is assured by the redundant interaction between apoptotic cell ligands and multiple receptor molecules present on the engulfing cell surface. This review concentrates on the molecular interactions operating in mammalian and non-mammalian systems for apoptotic cell recognition, as well as on the consequences of their signaling. Furthermore, some cellular models where the exposure of the phosphatidylserine (PS) phospholipid, a classical hallmark of the apoptotic phenotype, is not followed by cell death will be discussed.

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Molecule Possessing Ankyrin Repeats Induced by Lipopolysaccharide (MAIL)

Encyclopedia of Signaling Molecules ◽

10.1007/978-3-319-67199-4_102369 ◽

2018 ◽

pp. 3175-3175

Keyword(s):

Ankyrin Repeats

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Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

Marine Drugs ◽

10.3390/md19100535 ◽

2021 ◽

Vol 19 (10) ◽

pp. 535

Author(s):

Massimo Genovese ◽

Concetta Imperatore ◽

Marcello Casertano ◽

Anna Aiello ◽

Francesco Balestri ◽

...

Keyword(s):

Aldose Reductase ◽

Insulin Signalling ◽

Marine Invertebrate ◽

Tyrosine Phosphatase ◽

Competitive Inhibitor ◽

Dual Inhibitor ◽

In Silico Docking ◽

Insulin Signalling Pathway ◽

Depth Study ◽

Multiple Ligands

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

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