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Last update 08 May 2025

LNPEP

Last update 08 May 2025

Basic Info

Synonyms

angiotensin IV receptor, CAP, cystinyl aminopeptidase

+ [13]

Introduction

Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.

Drugs associated with LNPEP

BDM-76464

Target

LNPEP

Mechanism

LNPEP inhibitors

Active Org.

Institut Pasteur de Lille

Originator Org.

Institut Pasteur de Lille

Active Indication

Myocardial fibrosis [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BDM-92499

Target

LNPEP

Mechanism

LNPEP inhibitors

Active Org.

Institut Pasteur de Lille

Originator Org.

Institut Pasteur de Lille

Active Indication

Myocardial fibrosis [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with LNPEP

100 Translational Medicine associated with LNPEP

0 Patents (Medical) associated with LNPEP

664

Literatures (Medical) associated with LNPEP

27 Feb 2025·Journal of Medicinal Chemistry

Discovery of New Nanomolar Selective IRAP Inhibitors

Article

Author: Couturier, Cyril ; Warenghem, Sandrine ; van Endert, Peter ; Leroux, Florence ; Kraupner, Nicolas ; Roignant, Matthieu ; Ultré, Vincent ; Karroum, Nour Bou ; Lesire, Laetitia ; Lam, Bao Vy ; Rech, Alexandre ; Gealageas, Ronan ; Azaroual, Nathalie ; Deprez-Poulain, Rebecca ; He, Ben ; Mauvais, François-Xavier ; Deprez, Benoit

Among the M1 family of oxytocinase aminopeptidases, insulin-regulated aminopeptidase IRAP, is an emerging drug target implicated in various biological pathways and particularly in MHC-I antigen presentation through amino-terminal trimming of exogenous cross-presented peptides. A few series of inhibitors inspired either by angiotensin IV, one of IRAP substrates, or by bestatin a pan aminopeptidase inhibitor, have been disclosed. However, the variety and number of chemotypes remains relatively limited. Here we disclose the design and optimization of a series of hydroxamic acids IRAP inhibitors bearing a 5-substituted indole. Docking studies of the best compound 43 (BDM_92499), a single-digit nanomolar and selective inhibitor of IRAP, suggest an original binding mode and highlight the substituent on the indole and a primary amide as groups driving selectivity. Several inhibitors in the series displayed IRAP-dependent inhibition of antigen cross-presentation. These results pave the way to the development of novel therapeutic agents targeting IRAP.

01 Dec 2024·Alzheimer's & Dementia

Unveiling Proteomic Signatures of Tau Pathogenesis through Label‐Free Mass Spectrometry Analysis

Article

Author: Ikonomovic, Milos D ; Paljug, William R ; Sehrawat, Anuradha ; Karikari, Thomas K ; Abrahamson, Eric E ; Chen, Yijun ; Zeng, Xuemei ; Kofler, Julia

AbstractBackgroundNeurofibrillary tangles (NFT), consisting of hyperphosphorylated tau aggregates, are one of the major pathological hallmarks of Alzheimer’s disease (AD). The burden of NFTs correlates with cognitive decline, and in vivo detection of NFT may help predict the clinical progression of AD. Mass spectrometry‐based proteomic analysis of brain regions affected by NFTs holds the potential to unveil the molecular mechanisms underlying tau pathogenesis and uncover novel diagnostic/prognostic biomarkers and therapeutic targets.MethodPost‐mortem frozen samples of inferior temporal and middle frontal cortex were collected from 9 cases with different severity of tau pathology assessed by Braak NFT stage. Proteins were fractionated into three fractions using sequential extraction with lysis buffers with different solubility strengths (TBS, Na2CO3, and Urea), trypsin‐digested, and analyzed using label‐free nano‐flow liquid chromatography‐tandem mass spectrometry (nano LC‐MS/MS). Linear mixed models were employed to assess the significance of proteins showing a differential abundance in tissues with Braak NFT stages 0‐III and IV‐VI or displaying Braak stage‐dependent solubility changes.ResultA total of 64908 peptides originating from 5475 protein groups were identified through the analysis of 18 brain tissue samples. Differential proteomic analysis revealed several proteins with significantly varied abundance in tissues with different severity of tau pathology. The most significant proteins among these include COL25A1, SNRNP70, MDK, ASPRV1, CLMN, DOCK5, HTRA1, LNPEP, SQSTM1 and Aβ peptides. Additionally, a number of proteins exhibited Braak‐stage dependent solubility change; a significant subset of these proteins, including SNRNP70, SNRPGP15, PRPF6, SNRPE, SNRPD1, SNRPB, and SNRPD3, is involved in the spliceosome‐mediated mRNA splicing.ConclusionOur study reveals numerous proteins exhibiting a significant association with tau pathology. These results align well with published findings that suggest the involvement of alternative splicing in reprogramming gene expression in the pathogenesis of AD. Further validation will be needed to assess their potential as therapeutic targets and/or diagnostic/prognostic biomarkers for AD pathologies.

01 Nov 2024·Autophagy

Signal-Sustained Imaging of Mitophagy with an Enzyme-Activatable Metabolic Lipid Labeling Probe

Article

Author: Wang, Xunxiang ; Xu, Lichun ; Zou, Xiaoxue ; Gao, Lei ; Wen, Shixiong ; Han, Jiahuai ; Han, Shoufa ; Hu, Xiao

Imaging of mitophagy is of significance as aberrant mitophagy is engaged in multiple diseases. Mitophagy has been imaged with synthetic or biotic pH sensors by reporting pH acidification en route delivery into lysosomes. To circumvent uncertainty of acidity-dependent signals, we herein report an enzyme-activatable probe covalently attached on mitochondrial inner membrane (ECAM) for signal-persist mitophagy imaging. ECAM is operated via ΔΨm-driven accumulation of Mito-proGreen in mitochondria and covalent linking of the trapped probe with azidophospholipids metabolically incorporated into the mitochondrial inner membrane. Upon mitophagy, ECAM is delivered into lysosomes and hydrolyzed by LNPEP/leucyl aminopeptidase, yielding turn-on green fluorescence that is immune to lysosomal acidity changes and stably retained in fixed cells. With ECAM, phorbol-12-myristate-13-acetate (PMA) was identified as a highly potent inducer of mitophagy. Overcoming signal susceptibility of pH probes and liability of ΔΨm probes to dissipation from stressed mitochondria, ECAM offers an attractive tool to study mitophagy and mitophagy-inducing therapeutic agents.Abbreviations: Baf-A1, bafilomycin A₁; CCCP, carbonyl cyanide m-chlorophenylhydrazone; DBCO, dibenzocyclooctyne; ECAM, enzyme-activated probe covalently attached on mitochondrial inner membrane; GFP, green fluorescent protein; LAMP2, lysosomal associated membrane protein 2; LNPEP/LAP, leucyl and cystinyl aminopeptidase; PMA, phorbol-12-myristate-13-acetate; ΔΨm, mitochondrial transmembrane potential; RFP, red fluorescent protein; TPP, triphenylphosphonium.

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LNPEP

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