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Ectonucleotidase inhibitors: targeting signaling pathways for therapeutic advancement—an in-depth review

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Abstract

Ectonucleotidase inhibitors are a family of pharmacological drugs that, by selectively targeting ectonucleotidases, are essential in altering purinergic signaling pathways. The hydrolysis of extracellular nucleotides and nucleosides is carried out by these enzymes, which include ectonucleoside triphosphate diphosphohydrolases (NTPDases) and ecto-5′-nucleotidase (CD73). Ectonucleotidase inhibitors can prevent the conversion of ATP and ADP into adenosine by blocking these enzymes and reduce extracellular adenosine. These molecules are essential for purinergic signaling, which is associated with a variability of physiological and pathological processes. By modifying extracellular nucleotide metabolism and improving purinergic signaling regulation, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) inhibitors have the potential to improve cancer treatment, inflammatory management, and immune response modulation. Purinergic signaling is affected by CD73 inhibitors because they prevent AMP from being converted to adenosine. These inhibitors are useful in cancer therapy and immunotherapy because they may improve chemotherapy effectiveness and alter immune responses. Purinergic signaling is controlled by NTPDase inhibitors, which specifically target enzymes involved in extracellular nucleotide breakdown. These inhibitors show promise in reducing immunological responses, thrombosis, and inflammation, perhaps assisting in the treatment of cardiovascular and autoimmune illnesses. Alkaline phosphatase (ALP) inhibitors alter the function of enzymes involved in dephosphorylation reactions, which has an impact on a variety of biological processes. By altering the body’s phosphate levels, these inhibitors may be used to treat diseases including hyperphosphatemia and certain bone problems. This article provides a guide for researchers and clinicians looking to leverage the remedial capability of ectonucleotidase inhibitors in a variety of illness scenarios by illuminating their processes, advantages, and difficulties.

Graphical Abstract

Ectonucleotidases provide a visually appealing way to explore the complex world of extracellular nucleotide metabolism. The abstract’s central visual element is a stylized depiction of the cell membrane, emphasizing the surface-bound ectonucleotidases that are essential for controlling the amounts of extracellular nucleotides. The graphical section goes on to illustrate the wider consequences of ectonucleotidase activity, addressing a number of biological mechanisms, including the regulation of immune response and neurotransmission.

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Data availability

No datasets were generated or analyzed during the current study.

Abbreviations

ATP:

Adenosine triphosphate

NTPDase:

Ectonucleoside triphosphate di-phosphohydrolases

UDP:

Uridine-5′-diphosphate

h-NTPDase:

Human NTPDase

r-NTPDase:

Rat NTPDase

ENPP:

Ectonucleotide pyrophosphatase/phosphodiesterases

h-ENPP:

Human ENPP

ADP:

Adenosine diphosphate

ALP:

Alkaline phosphatases

TNAP:

Tissue-nonspecific alkaline phosphatase

QSAR:

Quantitative structure activity relationship

IALP:

Intestinal alkaline phosphatase

MDS:

Molecular dynamics simulations

b-TNAP:

Bovine-tissue non-specific ALP

BIALP:

Bovine intestinal alkaline phosphatase

NAD+ :

Nicotinamide-adenine dinucleotide

PPADS:

Pyridoxalphasposphate-6-azophenyl-2ʹ,4ʹ-di-sulphonic acid

AMP:

Adenosine monophosphate

RB-2:

Reactive blue 2

STING:

Stimulator of interferon genes

UTP:

Uridine-5′-triphosphate

LOD:

Limit of detection

cAMP:

Cyclic adenosine monophosphate

R 2 :

The correlation coefficient

PC-1:

Plasma cell membrane protein-1 (ENPP-1)

SAR:

Structure activity relationship

CYP:

Cytochrome P450

ADME:

Absorption, distribution, metabolism, and excretion

TME:

Tumor microenvironment

CoMFA:

Comparative molecular field analysis

MD:

Molecular dynamics

Q 2 :

Cross-validated coefficient

VS:

Virtual screening

HUVEC:

Human umbilical vein endothelial cells

hERG:

Human ether-a-go-go-related gene

PLAP:

Placental alkaline phosphatase

MOA:

Mechanism of action

CoMSIA:

Comparative molecular similarity index analysis

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Acknowledgements

The authors are grateful to Chemistry Department Quaid-i-Azam University Islamabad.

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Authors and Affiliations

  1. Department of Chemistry, Quaid-I-Azam University, Islamabad, 45321, Pakistan

    R. Huzaifa Sharafat & Aamer Saeed

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  1. R. Huzaifa Sharafat
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  2. Aamer Saeed
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Aamer Saeed: conceptualization, supervision, manuscript revision, and finalization.

Huzaifa Sharafat Ali: literature survey, manuscript writing, and structure drawing.

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Correspondence to Aamer Saeed.

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Sharafat, R.H., Saeed, A. Ectonucleotidase inhibitors: targeting signaling pathways for therapeutic advancement—an in-depth review. Purinergic Signalling (2024). https://doi.org/10.1007/s11302-024-10031-0

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