Our work spans over a decade and was initiated by a collaboration with late Dr Oikonomakos and continued with Dr E.D. Chrysina. Through this collaboration, a large number of GP synthetic inhibitors have been synthesized and studied through the structure-based intelligent drug-design process. These studies have led to a new family of GP catalytic site inhibitors of N¹-(β-D-glucopyranosyl)-N⁴-arylcytidines which have allowed us to study the favorable enzyme:inhibitor interactions deep within the catalytic site β-channel and have resulted in a number of new potent nanomolar inhibitors. The most potent inhibitor of this family has allowed us to probe the basicity of GP’s catalytic site through a collaboration with LIDYL, CNRS and ISOF, CNR.The work produced in this field of research, during the last decade+ is listed below as publications, presentations and proceedings as well as supervised Ph.D., M.Sc and undergraduate theses:

PUBLICATIONS IN SCIENTIFIC JOURNALS

45.    «Multiscale time-resolved fluorescence study of a glycogen phosphorylase inhibitor combined with quantum chemistry calculations» V. Maffeis, K. Mavreas, F. Monti, M. Mamais, 
T. Gustavsson, E. D. Chrysina, D. Markovitsi,* T. Gimisis* & A. Venturini* 2019, in press.                                                    https://doi.org/10.1039/C8CP07538G

42.      «A New Potent Inhibitor of Glycogen Phosphorylase Reveals the Basicity of the Catalytic Site»           M. Mamais, A. Degli Esposti, V. Kouloumoundra,
T. Gustavsson, F. Monti, A. Venturini,* E. D. Chrysina,* D. Markovitsi,* T. Gimisis* Chem. Eur. J. 2017, 23, 8800 – 8805.          https://doi.org/10.1002/chem.201701591                                
Featured in Frontispiece Cover:                                  https://doi.org/10.1002/chem.201783763

In this paper, a previously unknown property of the catalytic site of glycogen phosphorylase (GP) and specifically the catalytic site’s basicity has been revealed by using a photochemical fluorescent probe and at the same time one of the most potent catalytic site GP inhibitors that have been reported to date. The article was showcased by the journal with a frontispiece graphic.                                                                                                          

2.      «Synthesis of N⁴-aryl-β-D-glucopyranosylcytosines: a methodology study» Mamais, Μ.; Kouloumoundra, V.; Smyrli, E.; Grammatopoulos, P.; Chrysina, E.D.; Gimisis, T.* Tetrahedron Lett. 2015, 56, 5549–5552.

A synthetic methodology paper describing optimized conditions for obtaining the title compounds which are lead compounds for the proposed work.

3.      “Synthesis of N-glucopyranosidic derivatives as potential inhibitors that bind at the catalytic site of glycogen phosphorylase”Gimisis, T. Mini Rev. Med. Chem. 2010, 10(12) 1127-1138.

Invited Review with 60 refs.                                                                             21 Citations

4.      “Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure-Activity Relationships and X-ray Crystallographic Studies” Wen, X.; Sun, H.; Liu, J.; Cheng, K.; Zhang, P.; Zhang, L.; Hao, J.; Zhang, L.; Ni, P.; Zographos, S.E.; Leonidas, D.D.; Alexacou, K-M.; Gimisis, T.; Hayes, J.M.; Oikonomakos, J. Med. Chem. 2008, 51, 3540-3554.                                                                                                      >180 citations

5.      “FR258900, a Potential Anti-hyperglycemic Drug, Binds at the Allosteric Site of Glycogen Phosphorylase” C. Tiraidis, KM Alexacou, SE Zographos, DL Leonidas, T. Gimisis, NG Oikonomakos, Protein Sci. 2007, 16, 1773-1782.                                                                                                                                                 >17 Citations

6.      “Binding of Oxalyl Derivatives of β-D-glucopyranosylamine to Muscle Glycogen Phosphorylase b” Hadjiloi, T.; Tiraidis, C.; Chrysina, E. D.; Leonidas, D. D.; Oikonomakos, N. G.; Tsipos, P.; Gimisis, T. Bioorg. Med. Chem. 2006, 14, 3872-3882.          Featured on the Journal Cover Page                                                                       >12 Citations

 

PUBLICATIONS IN CONFERENCE PROCEEDINGS AND PRESENTATIONS

22.    «Synthesis of β-C-glucopyranosyl analogues of natural nucleosides »                             
K. Mavreas, T. Gimisis*           National Chemistry Symposium, AUTH, December 2016           

21.    «Glycogen Phosphorylase Inhibitors: Synthesis, Kinetics, Crystallography and in vivo Studies of New Hypoglycemic Agents» Thanasis Gimisis             Oral Presentation    in Program of Excellence “New drug transport systems in nanomedicine» NKUA, 13/7/2015.

20.    «4-arylamino-β-D-glucopyranosyl-pyrimidines: exploring the catalytic site of glycogen phosphorylase for the design of new antidiabetic agents”                   Poster presentation     Michail D. Mamais, Thanasis I. Gimisis, Evangelia D. Chrysina, 11^th Biology and Synchrotron Radiation International Conference (11^thBSR), Hamburg, 8-11/9/2013.

19.    “4-arylamino-β-D-glucopyranosyl-pyrimidines: exploring the catalytic site of glycogen phosphorylase” Michail D. Mamais, Thanasis I. Gimisis, Evangelia D. Chrysina,                   15th Hellenic Medicinal Chemistry Symposium, NRF, 25-27/5/2012.

18.    «4-arylamino-β-D-glucopyranosyl-pyrimidines: 4-αρυλαμινο-β-D-γλυκοπυρανοζυλο-πυριμιδίνες: exploring the catalytic site of glycogen phosphorylase » M.D. Mamais, T. Gimisis, E.D. Chrysina, 21^st National Chemistry Symposium, AUTH, 9-12/12/2011.

17.    “Exploring the Catalytic Site of Glycogen Phosphorylase with β-D-Glucopyranosyl-Nucleoside Inhibitors” T. Gimisis, (Invited Lecture), Structural Biology & Chemistry Symposium, Athens, Greece, 30 – 31 October, 2009.

16.    “Molecular modelling of β-D-glucose pyrimidine derivatives binding at the catalytic site of glycogen phosphorylase” Poster Presentation M. Mamais, J.M. Hayes, T. Gimisis, E.D. Chrysina, 3^rd National Organic Chemistry Symposium, NKUA, 15-17/10/2009.

15.    “Looking for potent inhibitors of glycogen phosphorylase: the structure-based ligand design approach in vitro & in silico” Lecture (L07)     E.D. Chrysina, J.M. Hayes, M. Mamais, E. Lazoura, T. Gimisis, 3^rd National Organic Chemistry Symposium, NKUA, 15-17/10/2009.

14.    “The biochemist’s routine is the organic chemist’s dream: Obtaining small molecule crystal data without crystallization. The case of glycogen phosphorylase inhibitors based on β-D-glucopyranosyl-nucleosides”               T. Gimisis, P. Grammatopoulos, M. Mamais, D. Sovantzis, K.-M. Alexacou, S. E. Zographos, D. D. Leonidas, E. Chrysina, J. M. Hayes, N. G. Oikonomakos,^†     4th Conference, Hellenic Crystallographic Association, Athens, 26 – 27/9/2008.

13.    «1+1=3: Synthesis of potential inhibitors of glycogen phosphorylase, solves problems in oxidative DNA damage and offers crystal structures without crystallization» T. Gimisis, Invited Lecture, Summer School «Organic Synthesis and Applications in Chemical Industry», Andros, 27–30/8/2008

12.    “Pentacyclic triterpenes, inhibitors of glycogen phosphorylase, as potential drugs for type 2 diabetes: X-ray crystallographic studies”   S. E. Zographos, D. D. Leonidas, K. M. Alexacou, T. Gimisis, J. M. Hayes, N. G.         Oikonomakos, X. Wen, H. Sun, J. Liu, K. Cheng, P. Zhang, L. Zhang, J. Hao, L. Zhang, P. Ni 7th Joint Meeting of GA, AFERP, ASP, PSE & SIF, Athens, Greece,3–8/8/2008       Published in: Planta Medica, 2008, 74, 1146-1147.                (I.F.: 2,089)

11.    “Synthesis and Protein Crystallography of Urea-Tethered Gluco-amino acids as Potential Inhibitors of Glycogen Phosphorylase” Poster Presentation     A. Stathi, D. Sovatzis, S. Zographos, D. Leonidas, N. Oikonomakos, T. Gimisis 13^th National  Pharmaceutical Chemistry Symposium, Athens, 13-15/3/2008.

10.    “Structure determination of DNA base lesions through oxidation of gluconucleosides and synthesis, coupled with protein crystallography” D. Stathis, T. Gimisis Lecture, 7^th Semi-Annual Meeting of RTN  program on “Selective Formation & Biochemistry of Oxidative Clustered DNA Damage” Plovdiv, Bulgaria, 2–6/6/2007.

9.      «Deciphering the structure of oxidative DNA damage products through independent synthesis and protein crystallography » Αθ. Γκιμήσης, Invited Lecture, 2^nd National Organic Synthesis Symposium, NKUA 19-21/4/2007

 Supervised Doctoral Theses within the subject of the proposal

1. Michail Mamais: “Synthesis, Kinetics and Crystallographic Study of potential inhibitors of glycogen phosphorylase” (Financed from Heraklitos II Program)        2010-2015

2. Virginia Kouloumoundra: “In vitro and in vivo study of synthetic inhibitors of glycogen phosphorylase as potential antidiabetic drugs”    2014-2016

3. Konstantinos Fioravantes Mavreas: “Synthesis and Study of C-glucopyranosides with possible pharmacological activity”             2016-present    IKY Fellowship recipient through the program:                                       “Strengthening human research potential through doctoral research”

 

Supervised Master’s Theses within the subject of the proposal

 11. Dimitrios Kontomarkos: “Synthesis of the aglycon and derivatives of known inhibitors of glycogen phosphorylase: Study of the effect of the inhibition constant”   2016

10. Konstantinos Fioravantes Mavreas: “Synthesis of C-glucopyranosyl analogues of natural nucleotides with potential pharmacological activity”                                  2016

9. Virginia Kouloumoundra: “Synthesis of novel strong inhibitors of glycogen phosphorylase using aryl-benzylamines”                                                                            2014

8. Evgenia Smyrli: “Synthesis of N⁴- and N³-aryl derivatives of β-D-glucopyranosyl pyrimidines as inhibitors of glycogen phosphorylase”                              2014

7. Michail Mamais: “In silico and in vitro studies of β-D-glucopyranosyl pyrimidines as potential antidiabetic drugs”                                                                     2009

6. Dimitrios Sovantzis: “Inhibitors of glycogen phosphorylase  as potential antidiabetic drugs” (Organic Chemistry Laboratory)                                                  2009

5. Aggeliki Stathi: “Synthesis of β-D-glucopyranosyl spiro nucleosides and β-D-glucopyranosyl-aminocarbonyl amino acids as potential inhibitors of glycogen phosphorylase”                                                                                          2008

4. Paschalis Grammatopoulos: “Synthesis of second generation inhibitors of glycogen phosphorylase based on β-D-glycopyranosyl uridine”                           2008

 

Supervised Undergraduate Theses within the subject of the proposal

 

15. Petros Baltimas, Adamantia Koroba: “Synthesis and spectral study of N¹-(β-D-glucopyranosyl)-N²-(5-benzimidazolyl)-cytosines as potential inhibitors of glycogen phosphorylase”                                                                                        2017

14. Irini Emmanouil, Michalis Minadakis: “Synthesis of β-D-glucopyranosyl pyrimidine derivatives as potential inhibitors of glycogen phosphorylase and photometric determination of the pKa of catalytic site inhibitors”                                                2017

13. Nikos Giannopoulos, Emmanouil Broumidis: “Development of a synthetic methodology for the synthesis of N¹-(β-D-glucopyranosyl)-N⁴-(2-aryl-1,3-dioxoisoindolin-5-yl)-cytosines”                                                                                                    2016

12. Giorgos Mazis, Giorgos Misiakos: “Synthesis of N¹-(β-D-glucopyranosyl)-N⁴-(3-acylphenyl) cytosines as potential inhibitors of glycogen phosphorylase”       2015

11. Aggelos Kitsikis, Basia Papanikolaou: “Development of a methodology for the synthesis of β-D-pyranosyl-diurea”                                                                           2015

10. Emilia Rigakou, Konstantina Iliou: “Synthesis of benzylamines from substituted benzaldehydes and their use in the synthesis of new inhibitors of glycogen phosphorylase”                                                                                          2015

9. Theodora Koutsikou, Anna Lada: “Synthesis of β-D-glucopyranosyl pyrimidines as potential inhibitors of glycogen phosphorylase”                                        2014

8. Ioli Aggeliki Kotsogianni-Teftsoglou, Konstantinos Fioravantes Mavreas: “Study of the substitution reaction of 4-position triazole pyrimidines by unreactive heterocyclic arylamines”                                                                                        2014

7. Eftychia Kavvadia: “Synthesis of 4-arylamino-β-D-glucopyranosyl pyrimidines, with the method of substitution of 1,2,4-triazoles, as inhibitors of glycogen phosphorylase”  2014

6. Stella Konstantopoulou: “Study of the 4-position substitution of β-D-glucopyranosyl uracil via 1,2,4 triazolyl derivatives”       2013

5. Maria Papageorgiou, Nadia Othman: “Synthesis of 4-aryloxy and 4-arylamine derivatives of N⁴-phenyl-N¹-(β-D-glucopyranosyl) cytosine as strong inhibitors of glycogen phosphorylase”        2012