Medicinal Chemistry Review of the NEET Protein Family

Apr 3, 2026ChemMedChem

Review of the Medicinal Chemistry of the NEET Protein Family

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Members of the NEET family of proteins are implicated in several age-related diseases, such as cancer and Alzheimer's.

The NEET family of proteins includes MitoNEET, which is involved in mitochondrial energy production and metabolism.
MitoNEET has been identified as an off-target of the antidiabetic drug pioglitazone.
CDGSH iron-sulfur domain-containing protein 2 is associated with anti-aging effects and Wolfram Syndrome 2.
CDGSH iron-sulfur domain-containing protein 3 is located in the mitochondrial matrix.
Developing ligands that interact with NEET proteins could provide pharmacological tools for studying their roles in disease.

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Members of the NEET family of proteins are of interest as drug targets in several age-related diseases, including cancer, diabetes, obesity, Alzheimer's and Parkinson's disease, stroke, and traumatic brain injury. These proteins share a CDGSH motif and redox-active [2Fe-2S] clusters. MitoNEET (CDGSH iron-sulfur domain-containing protein 1) is an outer mitochondrial membrane protein that was recently discovered as an off-target of the antidiabetic drug pioglitazone, and plays an essential role in mitochondrial bioenergetics, mitophagy, and iron metabolism. CDGSH iron-sulfur domain-containing protein 2 (nutrient-deprivation autophagy factor 1) is located on the endoplasmic reticulum and is found to be antiaging and associated with Wolfram Syndrome 2, while CDGSH iron-sulfur domain-containing protein 3 (mitochondrial inner NEET protein) is present in the mitochondrial matrix. In this review, we will evaluate the state of the field in the development of NEET protein interacting ligands, which can serve as pharmacological tools to study the biology/biochemistry of NEET family proteins in disease. The NEET family represents a novel class of drug targets, enabling the development of novel treatment modalities to modulate disease progression in various human disorders.

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Medicinal Chemistry Review of the NEET Protein Family

Abstract

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