CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders

Lu, Chenyang; Amin, M. Asif; Fox, David A.

doi:10.4049/jimmunol.1900868

Cited by 59 publications

(44 citation statements)

References 129 publications

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“…APN mainly cleaves the neutral amino acid from N-terminus of peptides and proteins. Consequently, it plays multifunctional roles in important biological processes, including antigen processing and presentation; tumor invasion and metastasis; cell adhesion and motility; and neurotransmitter degradation [9][10][11][12]. It also serves as a receptor for entry of certain coronaviruses [13,14].…”

Section: Introductionmentioning

confidence: 99%

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

et al. 2020

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A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results from the placement of aromatic side chain of an inhibitor. Interestingly, both enantiomers of the individual compounds are usually bound quite similarly.

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Section: Introductionmentioning

confidence: 99%

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

et al. 2020

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“…Increased expression is a hallmark of inflammation and has been observed in neurodegenerative disease, 8 and reduction of ANPEP activity has been investigated as a possible anti-inflammatory therapy. 9 Thus, elevated ANPEP levels could be associated with the development of PD and conceivably, through its role in inflammation, contribute to the severity of SARS-Cov-2 infection.…”

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confidence: 99%

The Human Coronavirus Receptor ANPEP (CD13) Is Overexpressed in Parkinson's Disease

et al. 2020

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The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), 1 a new human coronavirus (hCoV) strain. The neuroinvasive potential of SARS-CoV-2 2 and recent research linking advanced age and neurological disease to COVID-19 severity 3 raise concerns for patients with Parkinson's disease (PD), who appear to be particularly susceptible to worse outcomes from COVID-19. 4 Using a combination of publicly available and in-house RNA sequencing (RNAseq) data, we compared the abundance of the SARS-CoV-2 entry factors angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) between PD case and control whole blood (WB), frontal cortex (FC), and substantia nigra (SN) tissues. In addition, similar to others, 5 we expanded our investigation to include other hCoV entry factors, including aminopeptidase N (ANPEP, HCoV-229E), dipeptidyl peptidase 4 (DPP4, MERS-CoV), and glutamyl aminopeptidase (ENPEP), 6 all of which have been discussed as potential SARS-CoV-2 corecepetors. 6 We hypothesized that the expression of hCoV receptor genes in patients with PD differs from that of healthy individuals, potentially explaining the links between COVID-19 and worsened outcomes in PD. In line with available data (Genotype-Tissue Expression project 7), ACE2 was undetectable in WB in all cohorts. No expression was observed in SN tissue in PD cases or control subjects. Low ACE2 expression was observed in FC tissue, but in PD cases and control subjects the difference was not statistically significant (Fig. 1A), suggesting that ACE2 expression levels are not likely to be a significant contributor to the reported COVID-19 susceptibility in PD. 4 TMPRSS2 was also undetectable in WB and either brain tissue. DPP4 and ENPEP, although undetected in WB, may contribute to hCoV neuroinvasion 2 because both are expressed in FC and SN tissue; however, there was no significant difference in transcript abundance between PD cases and control subjects (P > 0.05; data not shown). Finally, we did not detect any significant correlation between genes, and no significant correlation was found between ACE2, DPP4 and ENPEP expression and age in cases or control subjects in any of the tissues examined (P > 0.05). Intriguingly, we saw significantly elevated ANPEP expression (adjusted P < 0.05) in PD cases compared with control subjects in all WB cohorts and FC tissue (Fig. 1B-G), but not in SN tissue (Fig. 1H), although we found no correlation between ANPEP expression and age in PD cases or control

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“…The mixture was intensively stirred for 30-60 min and the progress of the reaction was monitored by TLC chromatography (cyclohexane/ethyl acetate 4:1, v/v). Additionally, the aldehyde formation was observed by visualization of the TLC plate with 2,4-dinitrophenylhydrazine (2, indicator. After consumption of the substrate 50 mL of diethyl ether was added and the supernatant was filtrated through a silica gel with using diethyl ether as eluent.…”

Section: -(2-fluorophenyl)propanol (3b)mentioning

confidence: 99%

“…Accordingly, APNs represent the most widely scanning transmembrane proteases belonging to M1 aminopeptidases family, with capacity to control physiological processes based on the cleavage of neutral amino acid residues from peptide and protein substrates. Dysregulation of APNs expression is revealed as a disorder of metabolic pathways leading to the development of the pathologies related mainly with tumor-cell angiogenesis and metastasis, inflammatory diseases or neuropeptides dysfunctions [ 1 , 2 , 3 ]. It is worth to mention about their well-known function as a viral receptor, including human coronaviruses, where the CD13 amino acid fragment has been defined as a key for HCoV-229E infection [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases

et al. 2020

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A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

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CD13/Aminopeptidase N Is a Potential Therapeutic Target for Inflammatory Disorders

Cited by 59 publications

References 129 publications

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitution of the Aromatic Ring

The Human Coronavirus Receptor ANPEP (CD13) Is Overexpressed in Parkinson's Disease

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases

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