Faculty

Discovery of a new generation of angiotensin receptor blocking drugs: Receptor mechanisms and in silico binding to enzymes relevant to covid-19

Under the leading of collaborative research network  of Prof. J. Matsoukas it has been published in the  high esteem journal   the discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as “bisartans”. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2+ domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin cleavage site of the SARS-CoV-2 spike protein (residues 681–686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric “warhead” of PF-07321332, in its ability to disrupt the Cysteine Charge Relay System of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit COVID-19 infection, in bioassays, as effectively as PF-07321332 (paxlovid). (H. Ridway, G.J. Moore, T. Mavromoustakos, S. Tsiodras, I. Ligielli, K. Kelaidonis, C.T. Chasapis, L.K. Gadanec, V.G. Gorgoulis, J.M. Matsoukas. Discovery of a new generation of angiotensin receptor blocking drugs: Receptor mechanisms and in silico binding to enzymes relevant to covid-19\ Computational and Structural Biotechnology Journal, 20, 2091-2111 (2022),

 

The PhD candidate Irene Ligielli contributed to the publication of this work through the performance of molecular docking.

Recent research publication by NKUA on the role of polymorphic variation of the immune system on the production of antigenic petpides from SARS-CoV-2

Cellular adaptive immune responses are an important component of our immunity against SARS-CoV-2 and play important roles in vaccine efficacy and the development of severe COVID-19. The adaptive immune system can eradicate infected cells by recognizing small peptides (called antigenic peptides) presented on their surface, that originate from proteins of the virus that infects the cell. In a recent paper, published in the Journal of Biological Chemistry, scientists from the Chemistry Department of the National Kapodistrian University of Athens, the National Centre for Scientific Research “Demokritos” and the Biomedical Sciences Research Center “Alexander Fleming”, collaborated to demonstrate how common genetic variations (called polymorphisms) in a key enzyme that regulates recognition of infected cells by the immune system, can affect the generation of antigenic peptides from the spike glycoprotein of SARS-CoV-2. This frequent variability between individuals may contribute to the observed variable immune responses in COVID-19 and thus constitute a useful biomarker for severe COVID-19.

For more information, please contact Associate Prof. Efstratios Stratikos at estratikos@chem.uoa.gr or visit http://users.uoa.gr/~estratikos/

 

Figure: Heat-plot showing the processing of peptides form the SARS-CoV-2 glycoprotein by 10 different allotypes of Endoplasmic Reticulum Aminopeptidase 1.

 

Publication:

Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 Spike Glycoprotein

Stamatakis G, Samiotaki M, Temponeras I, Panayotou G, Stratikos E.*

Journal of Biological Chemistry, 2021, Oct 21:101329. doi: 10.1016/j.jbc.2021.101329.

 

A Recent Publication from the Laboratory of Organic Chemistry from the group of Associate Professor Christoforos Kokotos appeared in Green Chemistry (impact Factor 10.18) from the Royal Chemical Society

A recent publication from Nikoleta Spiliopoulou (PhD candidate) and Associate Professor Christoforos G. Kokotos entitled: «Photochemical metal-free aerobic oxidation of thiols to disulfides », which was carried out in the Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens appeared in the highly ranked international journal Green Chemistry (Impact factor 10.18).

The methodology (Green Chem., 2021, 23, 546) describes a novel and green organocatalytic photochemical transformation for the synthesis of both symmetrical and non-symmetrical disulfides from thiols. The developed protocol employs a small organic molecule (phenylglyoxylic acid) as the photoinitiator and is carried out under very mild conditions by irradiation employing either household lamps or sunlight. This novel methodology could find application in the synthesis of non-symmetrical disulfides, which very recently were introduced in literature as inhibitors of the SARS-Cov-2019 protein.

 

Publication Link: https://pubs.rsc.org/en/content/articlelanding/2021/GC/D0GC03818K

A research work in the field of Light Emitting Diodes (LEDs) was published in the international journal Nature Communications with the participation of Assoc. Prof. G. C. Vougioukalakis’ research team

Blue organic light emitting diodes (OLEDs) are highly important devices, in lighting, information storage, and display applications. Noble metal-based organometallic phosphors enable the fabrication of blue OLEDs with external quantum efficiencies (EQEs) exceeding 30%. However, the high cost and limited availability of noble metal phosphors have been the driving force for developing purely organic, thermally-activated delay fluorescent (TADF) emitters, relying on radiative deactivation from singlet states with 100% quantum efficiency. Through careful design and compositional engineering of such emitters, the EQEs of blue TADF OLEDs have steadily improved from 19.5% in 2014 to 38.4% in 2021.

In this work, a device combining a low triplet energy hole transporting interlayer with high mobility (two novel fluorinated-thiophene-quinoxaline copolymers were employed), with an interface exciplex that confines excitons at the emissive layer/electron transporting material interface (combination of donor-acceptor bis(diphenylphosphine oxide)dibenzofuran –DBFPO– with diphenyl[4-(triphenylsilyl)phenyl]phosphine oxide -TSPO1- as acceptor) was developed. Blue TADF OLEDs with an external quantum efficiency of 41.2% were thus successfully fabricated. This approach paves the way for further progress through exploring alternative device engineering approaches, instead of solely focusing on the demanding synthesis of organic compounds with complex architectures.

The work was the result of an international interdisciplinary collaboration of research groups based in Greece (NKUA, NCSR “Demokritos”, and NHRF), South Korea (POSTECH), UK (Imperial College London), and Brazil (CPGEI). The NKUA research group (Post-doctoral Fellow Dr. G. Rotas and Associate Professor G. C. Vougioukalakis) synthesized and characterized certain photoactive organic molecules used in the study.

Visit Associate Professor G. C. Vougioukalakis’ research group webpage for more info on this and other works: http://users.uoa.gr/~vougiouk

Contribution of Organic Chemistry in the understanding of the Role of Cholesterol in Hypertension (T. Mavromoustakos group)

Cholesterol is an essential component of our cellular membranes. Cholesterol is responsible for a plethora of functions in cellular membranes. It regulates their fluidity so that they respond in temperature changes without being subjected to damages while it also affects the way in which pharmaceutical molecules act on transmembrane receptors. Such a receptor is AT1, where the antihypertensive molecules, sartans, bind in order to block the detrimental action of the octapeptide hormone angiotensin II, in pathological conditions. The way in which sartans bind to the receptor is unknown in the molecular level. They could bind directly to the receptor via the extracellular area or indirectly through initial penetration in the bilayers and subsequent lateral diffusion to the receptor’s binding site. Cholesterol is shown to allosterically interact with the receptor, possibly facilitating the binding of AT1 antagonists. On the other hand, it is shown to retard the diffusion of the drugs in the lipid bilayers. This dual role of cholesterol which was highlighted by our research group, during the PhD thesis of Mrs Sofia Kiriakidi, in collaboration with the research groups of Assoc. Prof. A. Tzakos and Researcher B’  Z. Cournia, opens up new horizons for the understanding of the sartan action mechanism in the molecular level and the rational design of novel drugs.

This work was published in the Computational and Structural Biotechnology Journal with an impact factor of 6.018.

Kiriakidi S, Chatzigiannis C, Papaemmanouil C, Tzakos AG, Cournia Z, Mavromoustakos T. Interplay of cholesterol, membrane bilayers and the AT1R: A cholesterol consensus motif on AT1R is revealed. Comput Struct Biotechnol J. 2020 Dec 3;19:110-120. doi: 10.1016/j.csbj.2020.11.042. 

Feature of a Publication of the Laboratory of Organic Chemistry (by the Group of Assoc. Prof. Victoria Magrioti)

The research group of Assoc. Prof. V. Magrioti of the Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens in collaboration with the group of Dr J.-F. Cavalier and Dr. S. Cannan of the Laboratoire d’Ingénierie des Systèmes Macromoléculaires, Institut de Microbiologie de la Méditerranée, CNRS Marseille, France have published a series of medium and long-chain β-lactones in order to study their antimycobacterial activity (https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201800720). Recently, this publication has been chosen to feature in Hot Topics 2020: Antimicrobials (bit.ly/cmc-2020-Antimicrobials) by the journal ChemMedChem. ChemMedChem is one of the most important journals that publish original research work on Medicinal Chemistry.

This project is part of the global research for novel agents against tuberculosis that is caused by Mycobecterium tuberculosis, either the natural strain or mutant strains that present resistance against known drugs.

The designed and synthesized b-lactones were either monosubstituted at the α- or β-position of the β-lactone ring or α,β-disubstituted. They were studied as racemic mixtures and several of them presented interesting activity against Mycobecterium tuberculosis and marinum, but minimal to no activity against M. abscessus. The collaboration of the two research groups continues by studying the antimycobacterial activity of optically pure β-lactones, as well as of other types of organic compounds.

For more information, please contact Assoc. Prof. Victoria Magrioti (vmagriot@chem.uoa.gr) or visit http://users.uoa.gr/~vmagriot/ 

Contribution of the Laboratory of Organic Chemistry in the effort to fight diseases (T. Mavromoustakos Group)

1. Enhancing the treatment of glioblastoma polymorphism through rational design of the quercetin-losartan hybrid composition.

An article has been recently published in the journal Free Radical Biology and Medicine 160 (2), 391-402 (impact index in 2019 6.17 and last five years 6.46), entitled “Enhancing the treatment of polio glioblastoma through a quercetin hybrid –losartan”. In this article the team of the Laboratory of Organic Chemistry collaborated under the guidance of T. Mavromoustakos where rational drug design through Molecular Docking was performed, the team of Associate Professor A. Tzakos, under whose guidance the hybrid molecule was synthesized, conducting biological tests by the Departments of Medicine, Molecular Biology and Biotechnology and Biology of the University of Ioannina, the John Fulcher Neuro-Oncology Laboratory, Imperial College London, Hammersmith Hospital, London, UK and Monash Biomedicine Discovery Institute and Department of Biochemistry and M , Monash University, Clayton, VIC, 3800, Australia.

A brief summary of the research work is given below: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.

2. Discovery of chemical compounds with dual inhibitory activity of TNF and RANKL, two proteins that are major targets for the treatment of chronic inflammatory diseases.

Distinction of published work: G. Melagraki, E. Ntougkos, V. Rinotas, C. Papaneophytou, G. Leonis, T. Mavromoustakos, G. Kantopidis, E. Douni, A. Afantitis, G. Kol. Cheminformatics-aided discovery of small-molecule protein-protein interaction (PPI) dual inhibitors of Tumor Necrosis Factor (TNF) and receptor activator of NF-κB B ligand (RANKL). PLOS Computational Biology 13 (4), e1005372 (2017). (I.F 2020 4.380). This article is among the top 10% published in the internationally renowned journal PLOS Computational Biology published in 2017.

Congratulations Thomas!
Your article is among the top 10% most cited PLOS Computational Biology papers published in 2017.

Cheminformatics-Aided Discovery of Small-Molecule Protein-Protein Interaction (PPI) Dual Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NFKB Ligand (RANKL)
CITED 21 TIMES as of July 2020.

Share the good news with your social networks:

 

The Most Recent Publication from the Laboratory of Organic Chemistry of the National and Kapodistrian University of Athens in the Top 10% of the Most Downloaded Papers in the Highly Prestigious Journal “Angewandte Chemie International Edition”

On April 30th 2020, Wiley-VCH – European Chemical Society Publishing announced the top downloaded publications in recent publication history. The most recent publication from the Research Group of Assistant Professor Christoforos Kokotos is among the top 10% of the most downloaded papers in the highly prestigious scientific journal Angewandte Chemie International Edition (impact factor 12.24).

This study introduces a new chemical reaction for the synthesis of ketones from aldehydes and olefins via the development of a “green”, environment-friendly, organocatalytic (metal-free) photochemical organic transformation. For more details regarding the study, please read the following article link https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201912214 or http://www.chem.uoa.gr/?p=63347&lang=en

Two Recent Publications from the Laboratory of Organic Chemistry of NKUA in the Top 10% of the Most Downloaded Papers in the Journals “European Journal of Organic Chemistry” and “ChemCatChem”

On April 30th 2020, Wiley-VCH – European Chemical Society Publishing announced the top downloaded publications in recent publication history. Two publications from the Research Group of Assistant Professor Georgios C. Vougioukalakis are among the top 10% of the most downloaded papers in the scientific journals European Journal of Organic Chemistry and ChemCatChem.

 

Both publications are in the field of Organic Chemistry and Sustainable Catalysis. The first work is entitled “A Sustainable, User-Friendly Protocol for the Pd-Free Sonogashira Coupling Reaction” with authors Aggeliki A. Liori, Ioannis K. Stamatopoulos, Argyro T. Papastavrou, Afroditi Pinaka, and Georgios C. Vougioukalakis. It discusses the development of a new catalytic system for the palladium-free Sonogashira coupling reaction, based on a widely available, low-cost, non-toxic copper salt. The Sonogashira coupling reaction is widely utilized in industry and academia for the synthesis of compounds with important technological and biological applications. You can access this work by clicking: https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201800827

 

The second work is entitled “Unprecedented Multicomponent Organocatalytic Synthesis of Propargylic Esters via CO2 Activation” with authors Argyro T. Papastavrou, Martin Pauze, Enrique Gómez-Bengoa, and Georgios C. Vougioukalakis. It discusses an innovative, efficient, and straightforward organocatalytic method for the direct, multicomponent carboxylation of terminal alkynes with CO2 and organochlorides, towards propargylic esters, for the first time. Given that CO2 is the major greenhouse effect gas, its monetization towards the preparation of useful chemicals is of outmost importance, especially when this is achieved in a highly sustainable manner. This work can be accessed by clicking: https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cctc.201900207

 

More information about these works and other research projects implemented in the Research Group of Assistant Professor Georgios C. Vougioukalakis can be found here: http://users.uoa.gr/~vougiouk

 

 

THE INTRODUCTION OF A NOVEL CHEMICAL REACTION FROM THE GROUP OF ASSISTANT PROFESSOR CHRISTOFOROS KOKOTOS OPENS NEW AVENUES FOR THE SYNTHESIS OF HIGH ADDED VALUE CHEMICALS

The development of a “green”, environment-friendly, organocatalytic (metal-free) photochemical organic transformation for the synthesis of ketones from the reaction between aldehydes and unactivated olefins was reported by the group of Assistant Professor Christoforos Kokotos. The publication entitled: «Green Metal-Free Photochemical Hydroacylation of Unactivated Olefins», which was carried out by PhD candidate Errika Voutyritsa and Assistant Professor Christoforos Kokotos in the Laboratory of Organic Chemistry of the Department of Chemistry of the National and Kapodistrian University of Athens, was published in the highly ranked international journal Angewandte Chemie. Angewandte Chemie, a journal of the Wiley publishing house, constitutes a top international journal in Chemistry with a high impact factor (12.24). Publication Link: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201912214

The methodology describes a novel organic reaction that employs a small organic molecule (phenylglyoxylic acid) as the photoinitiator, water as the solvent and is carried out under very mild conditions by irradiation employing either household lamps or sunlight. The reaction constitutes a novel C-H activation methodology that does not require metal catalysts or directing groups and can be employed in a plethora of subtrates. The reaction and its products are of high importance for the Chemical Industry and especially the Pharmaceutical Industry. Key role in the success of the work was the study of the reaction mechanism in detail. This new synthetic methodology is expected to open new avenues in Organic Synthetic Chemistry and will find applications in the synthesis of high added value chemicals and pharmaceuticals, as well as in the synthesis of natural products.

Skip to content