Athanasios Papakyriakou

Athanasios Papakyriakou
National Center for Scientific Research Demokritos | ncsr · Institute of Biosciences and Applications (IB-A)

PhD Chemistry

About

100
Publications
12,647
Reads
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1,768
Citations
Additional affiliations
September 2018 - present
National Center for Scientific Research Demokritos
Position
  • Senior Researcher
September 2016 - present
University of Southampton
Position
  • Marie Curie Research Fellow
June 2012 - June 2014
University of California, San Diego
Position
  • Researcher
Education
April 2001 - May 2004
March 1999 - April 2001
September 1994 - February 1999

Publications

Publications (100)
Article
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Receptor activator of nuclear factor-κB ligand (RANKL) constitutes the master mediator of osteoclastogenesis, while its pharmaceutical inhibition by a monoclonal antibody has been approved for the treatment of postmenopausal osteoporosis. To date, the pursuit of pharmacologically more favorable approaches using low-molecular-weight inhibitors has b...
Article
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Insulin-Regulated aminopeptidase (IRAP) is a zinc-dependent aminopeptidase with several important biological functions and is an emerging pharmaceutical target for cognitive enhancement and immune system regulation. Aiming to discover lead-like IRAP inhibitors with enhanced selectivity versus homologous enzymes, we targeted an allosteric site at th...
Article
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Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Compl...
Article
Full-text available
Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) play important roles in the generation of antigenic peptides presented by Major Histocompatibility Class I (MHCI) molecules and indirectly regulate adaptive immune responses. Although the discrete function of these enzymes has been extensively characterized, recent reports have suggest...
Article
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In order to gain a deeper understanding of the recently emerged and highly divergent Omicron variant of concern (VoC), a study of amino acid substitution (AAS) patterns was performed and compared with those of the other four successful variants of concern (Alpha, Beta, Gamma, Delta) and one closely related variant of interest (VoI—Lambda). The Spik...
Article
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Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled wit...
Article
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The antiplatelet and antithrombotic activity of a novel organometallic rhodium(I) complex of the formula [Rh(cod)Cl(tpc)] (1) (cod = cis‐1,5‐cyclooctadiene; tpc = methyl 2‐amino‐4‐(diethylamino)‐thieno‐[2,3‐d]‐pyrimidine‐6‐carboxylate) was investigated. Complex 1 was easily synthesized by a one‐pot, high‐yield reaction and was fully characterized b...
Article
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Background and aims: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes...
Article
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An amendment to this paper has been published and can be accessed via the original article.
Article
Full-text available
Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled wit...
Article
Full-text available
The high-resolution X-ray crystal structures of the adducts formed between the “half sandwich”-type Ru(II) coordination compound [RuII(1,4,7-trithiacyclononane)(ethane-1,2-diamine)Cl]+ and two proteins, namely hen egg-white lysozyme and proteinase K, are presented. The structures unveil that upon reaction with both enzymes the Ru(II) compound is co...
Article
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Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator associated to diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis and canc...
Article
Full-text available
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI–peptide complexes, b...
Article
Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that optimizes the peptide cargo of major histocompatibility class I (MHC-I) molecules and regulates adaptive immunity. It has unusual substrate selectivity for length and sequence, resulting in poorly understood effects on the cellular immunopeptidome. To understand substrat...
Article
The oxytocinase subfamily of M1 aminopeptidases consists of three members, ERAP1, ERAP2 and IRAP that play several important biological roles, including key functions in the generation of antigenic peptides that drive human immune responses. They represent emerging targets for pharmacological manipulation of the immune system, albeit lack of select...
Article
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CD4⁺ T-cells recognize peptide antigens, in the context of human leukocyte antigen (HLA) class II molecules (HLA-II), which through peptide flanking residues (PFRs) can extend beyond the limits of the HLA-binding. The role of the PFRs during antigen recognition is not fully understood; however, recent studies have indicated that these regions can i...
Article
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The efficacy of cancer immunotherapy, including treatment with immune-checkpoint inhibitors, often is limited by ineffective presentation of antigenic peptides that elicit T-cell-mediated anti-tumor cytotoxic responses. Manipulation of antigen presentation pathways is an emerging approach for enhancing the immunogenicity of tumors in immunotherapy...
Article
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The α9 subunit of nicotinic acetylcholine receptors (nAChRs) exists mainly in heteropentameric assemblies with α10. Accumulating data indicate the presence of three different binding sites in α9α10 nAChRs: the α9(+)/α9(-), the α9(+)/α10(-), and the α10(+)/α9(-). The major role of the principal (+) side of the extracellular domain (ECD) of α9 subuni...
Article
Full-text available
Endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 process N-terminally extended antigenic precursors for optimal loading onto major histocompatibility complex class I (MHC I) molecules. We and others have demonstrated that ERAP1 processes peptides bound to MHC I, but the underlying mechanism is unknown. To this end, we utilized single-chain...
Article
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Zebrafish has emerged as a powerful model organism for high throughput drug screening. Several morphological criteria, transgenic lines and in situ expression screens have been developed to identify novel bioactive molecules and their mechanism of action. Here we used the inhibition of melanogenesis during early zebrafish embryo development to iden...
Article
The cell wall peptidoglycan is recognized as a primary target of the innate immune system and usually its disintegration results in bacterial lysis. Bacillus cereus, a close relative of the highly virulent Bacillus anthracis, contains 10 polysaccharide deacetylases. Among these, the peptidoglycan N-acetylglucosamine deacetylase Bc1974 is the highes...
Article
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The enantioselectivity of β-cyclodextrin (β-CD) towards L- and D-N-acetyltryptophan (NAcTrp) has been studied in aqueous solution and the crystalline state. NMR studies in solution show that β-CD forms complexes of very similar but not identical geometry with both L- and D-NAcTrp and exhibits stronger binding with L-NAcTrp. In the crystalline state...
Data
Experimental data containing geometry data of the β-CD hosts; H-bonding interactions in the β-CD dimer; NMR data (Job plots and 2D maps of the observed dipolar interactions); packing, origin selection and comparison of monomeric β-CD complexes; modeling results of D-NAcTrp/β-CD.
Article
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Antigenic peptides presented by the major histocompatibility complex class I (MHC-I) molecules for recognition by cytotoxic T-lymphocytes are processed by members of the oxytocinase sub-family of M1 aminopeptidases ERAP1, ERAP2, and IRAP. These three homologous zinc metallopeptidases trim N-terminally extended precursor antigenic peptides down to t...
Article
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Recently, it was discovered that exposure to mainstream antibiotics activate numerous bacterial ri-boregulators that control antibiotic resistance genes including metabolite-binding riboswitches and other transcription attenuators. However, the effects of commonly used antibiotics, many of which exhibit RNA-binding properties, on the widespread T-b...
Article
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The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor–alpha (TNF-α; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solu...
Article
Protein phosphorylation is the most frequent eukaryotic post-translational modification and can act as either a molecular switch or rheostat for protein functions. The deliberate manipulation of protein phosphorylation has great potential for regulating specific protein functions with surgical precision, rather than the gross effects gained by the...
Article
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The clinical efficacy of antiangiogenic small molecules (e.g., sunitinib) in breast carcinoma has largely failed with substantial off-target toxicity. We rationally designed and evaluated preclinically a novel sunitinib analogue, SAP, with favourable pharmacological properties and the ability to be readily conjugated to a targeting peptide or antib...
Article
Full-text available
Insulin-regulated aminopeptidase (IRAP) is an enzyme with several important biological functions that is known to process a large variety of different peptidic substrates although the mechanism behind this wide specificity is not clearly understood. We describe a crystal structure of IRAP in complex with a recently developed bioactive and selective...
Article
Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adap...
Article
Full-text available
Protein phosphorylation is the most frequent eukaryotic post-translational modification and can act as either a molecular switch or rheostat for protein functions. The deliberate manipulation of protein phosphorylation has great potential for regulating specific protein functions with surgical precision, rather than the gross effects gained by the...
Article
Full-text available
Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is an intracellular enzyme important for the generation of antigenic epitopes and class I MHC-restricted adaptive immune responses. ERAP1 processes a vast variety of different peptides but still shows length and sequence selectivity although the mechanism behind these properties is poorly understood. X...
Article
The oxytocinase subfamily of M1 aminopeptidases, consisting of ER aminopeptidase 1 (ERAP1), ER aminopeptidase 2 (ERAP2) and insulin-regulated aminopeptidase (IRAP), plays critical roles in the generation of antigenic peptides and indirectly regulates human adaptive immune responses. We have previously demonstrated that phosphinic pseudotripeptides...
Article
Full-text available
PNLDC1 is a homologue of poly(A) specific ribonuclease (PARN), a known deadenylase with additional role in processing of non-coding RNAs. Both enzymes were reported recently to participate in piRNA biogenesis in silkworm and C. elegans, respectively. To get insights on the role of mammalian PNLDC1, we characterized the human and mouse enzymes. PNLD...
Article
Liposomes containing lysophospholipids are intensively studied as drug delivery systems that are stable at normal body temperature but exhibit fast release of their drug load at slightly elevated temperatures. In this study, the stability and release properties of dipalmitoylglycerophosphocholine (DPPC)-based liposomes incorporating the commonly us...
Article
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We employed virtual screening followed by in vitro evaluation to discover novel inhibitors of ER aminopeptidase 1, an important enzyme for the human adaptive immune response that has emerged as an attractive target for cancer immunotherapy and the control of autoimmunity. Screening hits included three structurally-related compounds carrying the (E)...
Article
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The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogs of a clinically established antiangiogenic compound (sunitinib) from which a lead candidate (SAN1...
Article
A convenient synthesis of imatinib, a potent inhibitor of ABL1 kinase and widely prescribed drug for the treatment of a variety of leukemias, was devised and applied to the construction of a series of novel imatinib analogues featuring a number of non-aromatic structural motifs in place of the parent molecule's phenyl moiety. These analogues were s...
Article
Full-text available
Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepare...
Article
Full-text available
Inhibition of Tumor Necrosis Factor (TNF) production or function by small molecules has become a major focus in the pharmaceutical industry for the treatment of Rheumatoid Arthritis. In this study, a series of 39 novel SPD-304 analogs were designed, synthesized and evaluated as TNF inhibitors. Our results show that small structural changes produce...
Article
Full-text available
p>The α9α10 nicotinic acetylcholine receptor (nAChR) was first identified in the auditory system, where it mediates synaptic transmission between efferent olivocochlear cholinergic fibers and cochlea hair cells. This receptor gained further attention due to its potential role in chronic pain and breast and lung cancers. We previously showed that α-...
Article
Full-text available
The α9α10 nicotinic acetylcholine receptor (nAChR) was first identified in the auditory system, where it mediates synaptic transmission between efferent olivocochlear cholinergic fibers and cochlea hair cells. This receptor gained further attention due to its potential role in chronic pain and breast and lung cancers. We previously showed that α-co...
Article
Members of the oxytocinase sub-family of M1 aminopeptidases (ERAP1, ERAP2 and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demons...
Article
A PC bond-forming reaction between silyl phosphonites and Morita–Baylis–Hillman acetates (MBHAs) is explored as a general alternative towards medicinally relevant β-carboxyphosphinic structural motifs. Conversion rates of diversely substituted MBHAs to phosphinic acids 9 or 14 that were recorded by using 31P NMR spectroscopy revealed unexpected rea...
Article
Background and purpose: Fibrates are a class of drugs widely used to treat dyslipidemias. They regulate lipid metabolism and act as peroxisome proliferator (PPAR) α receptor agonists. Clinical trials demonstrate that besides changes in lipid profiles fibrates decrease the incidence of cardiovascular events, with gemfibrozil exhibiting the most pron...
Article
Full-text available
Platelet Activating Factor (PAF), the most potent inflammatory mediator, is involved in a wide range of pathophysiological actions. PAF signal transduction is mediated through PAF receptors (PAFR) that are coupled with several isoforms of G-proteins. PAF hydrolysis is mediated through specific enzymes clustered as PAF acetylhydrolases (PAF-AH). The...
Article
SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs...
Article
Full-text available
Abstract Small molecules that inhibit angiogenesis are attractive drug candidates for cancer, retinopathies, and age-related macular degeneration. In vivo, phenotypic screening in zebrafish (Danio rerio) emerges as a powerful methodology to identify and optimize novel compounds with pharmacological activity. Zebrafish provides several advantages fo...