RDS Drug Design & Development (CHIM/08)

Attività di ricerca

The activity of RDS DDD is based on drug design and discovery (DDD), mainly focused on the research of new antimicrobial and antitumor agents. In particular, the field of antiviral agents is aimed to the discovery of novel classes of HIV agents, like inhibitors of integrase enzyme, both catalytic site ligands or inhibitors of interaction of IN with cofactors, inhibitors of ribonucealse H function of the reverse transcriptase and NNRTI. The chemical classes of these inhibitors include polyhydroxylated aromatics, aryl-thio-pyrroles, diketoacids, quinolonyl non DKA and pyrrolylpyrazoles. DDD was also performed to obtain agents active against viruses like poliovirus, chikungunya and HCV. Studies on agents active against SARSCoV2 enzymatic target (helicase, MPro, ACE/spike interaction, polymerase) are also in development in collaboration with Pasteur Institut of Paris.

Antiprotozoal agents have been designed to fight pathogens like T. cruzi and Leishmania. Azoles targeting the protozoal demethylases have been developed as potent anti Tc agents active in vivo on mice models as well as innovative agents targeting the trypanothione metabolism of Leishmania.

Antifungal agents have been also designed and synthesized like analogues of bifonazole, ketoconazole, miconazole and metal chelator compounds.

Zinc chelators have been studied as inhibitors of ZnuABC transporter that has important role in the pathogenicity of Gram-negative bacteria. Also Zinc chelators were designed to obtain metallo-betalactamase inhibitors.

Moreover, antitumor agents like pyrimidine and pyrrole benzazolyl-ureas derivatives have been designed and proven active as inhibitors of tubulin assembling, heparanase and terminal transferases.

Compound active on CNS have been also obtained as multitarget anti-Alzheimer agents, including cholinesterase inhibitors and metal chelators.

Part of the activity is also aimed to the extraction and the characterization of natural compounds as antimicrobial or antitumor activities.

Cooperation with Companies is always active to develop anti-inflammatory, antibaterial, anti-Alzheimer, antimalarial agents and ligands of 5-HT4 receptors.

Collaborazioni nazionali e internazionali

Katholieke Universiteit Leuven, Belgium (Johan Neyts, Zeger Debyser)
CNRS - Université de Bordeaux France (M. Metifiot, M.L .Andeola)
Paris Pasteur Institut, Paris France (F. Agou, R. Felix, M. Delarue)
Swiss Tropical Institute, Basel, Svizzera (Dott. Reto Brun, Marcel Kaiser , Pascal Mäser)
University of California, La Jolla, San Diego, USA (Prof. Larissa Podust, Gareth K. Jennings )
Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States (Eric Rhoden, M. Steven Oberste)
National Institute of Health, Bethesda, USA (Prof. Yves Pommier)
National Institute of Health, Frederick, USA (Prof. Stuart Le Grice)
Department of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Catalonia, Spain (Alba Espargaró, Raimon Sabatè)

Strumentazione

UniqSys Flow Chemistry Reactor
CEM Discover Microwave reactor
Sicore Buchi parallel synthesis reactor
HPLC (Shimadzu)
Mass Spectrometer (Thermo) – HPLC-MS
FT-IR (Perkin-Elmer)
ATAGO Polarimeter AP 300
Liophilizator Martin Christ ALPHA 1-2 LD PLUS, pump Vacuubrand RZ6XS 96
Smal Ultra Low Freezer B3550 FRK

Settori ERC

PE5_18 Medicinal Chemistry
LS7 - Diagnostic tools, therapies and public health: aetiology, diagnosis and treatment of disease, public health, epidemiology, pharmacology, clinical medicine, regenerative medicine, medical ethics.
PE5_11 Biological chemistry

Finanziamenti

Grants (2019-2020):

2019. Istituto Pasteur International Network - RIIP: DrugDesign_SARS2.
2019. “Anna Tramontano” Pasteur Institut Fondazione Cenci Boilognetti funding. “Targeting Trypanosomatids sterol biosynthesis and thiol redox metabolism key enzymes for lead drug discovery”
2019. Targeting poverty-related co-infectious diseases through drug lead optimization and combination studies. Ateneo Progetti medi.
2020. Design and Development of novel Heparanase inhibitors able to modulate autophagy. Ateneo Progetti medi.
2020. Multitarget directed ligands approach per lo sviluppo di nuovi potenziali agenti nella terapia del morbo di Alzheimer. Progetti di Ateneo Piccoli. RP120172B31884B1
2019. Sviluppo di nuovi multitarget directed ligands come potenziali agenti nella terapia del morbo di Alzheimer. Progetti di Ateneo Piccoli. RP11916B6ECA91C1.

Grants (2015-2018):

COMBINED HIGHLY ACTIVE ANTI-RETROVIRAL MICROBICIDES 242135 (CHAARM). FP7-HEALTH 2009.European Microbicides Development Programme to 30-06-2015
"Targeting Trypanosomatids sterol biosynthesisand thiol redox metabolism key enzymes for lead drug discovery” C26H15WYPW Progetti di Ricerca Grandi - Progetti Grandi" Anno 2015. PI Prof. Roberto Di Santo from 01-11-2015 to 31-10-2016
“Progettazione e sintesi di nuovi inibitoridell’Eparanasi, come potenziali agenti anti-metastatici”. codice CHR090100 Dott.Giannini)STRCH/14/RA/98 2014-2015 from 01-01-2014 to 01-01-2015
Istituto Pasteur Cenci-Bolognetti (2014-17)“Dual IN and RNase H inhibitors to defeat HIV”. from 01-01-2014 to 01-01-2017
“Progettazione e sintesi di nuovi inibitori dell’Eparanasi, come potenziali agenti anti-metastatici”. codice CHR090100 Dott.Giannini) STRCH/15/RA/118 2015-2016 from 01-01-2015 to 01-01-2016
Progetti di Ricerca Grandi – “Progetti Grandi" anno 2017 dal titolo Novel selective inhibitors of ribonuclease H function of the HIV-1 reverse transcriptase enzyme - n. protocollo RG11715C7EB6A275 from 10-11-2017

Pubblicazioni

Publication (2015-2018):

1. Saccoliti F, Angiulli G, Pupo G, Pescatori L, Madia VN, Messore A, Colotti G, Fiorillo A, Scipione L, Gramiccia M, Di Muccio T, Di Santo R, Costi R, Ilari A. Inhibition of Leishmania infantum trypanothione reductase by diaryl sulfide derivatives. J. Enzyme Inhib. Med. Chem. 2017, 32, 304-310. DOI: 10.1080/14756366.2016.1250755.

2. I. V. Getun, Z., Wu, M. Fallahi, S. Ouizem, Q. Liu, W. Li, R. Costi, W. R. Roush, J. L. Cleveland, P. R. Bois. Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hot Spots. Mol. Cell. Biol. 2017, 37, e00942-15. DOI: 10.1128/MCB.00942-15.

3. D. De Vita, G. Simonetti, F. Pandolfi, R. Costi, R. Di Santo, F. D. D’Auria, L. Scipione. Exploring the anti-biofilm activity of cinnamic acid derivatives in Candida albicans. Bioorg. Med. Chem. Lett. 2016, 26, 5931-5935. DOI: 10.1016/j.bmcl.2016.10.091.

4. D. De Vita, F. Pandolfi, L. Ornano, M. Feroci, I. Chiarotto, I. Sileno, F. Pepi, R. Costi, R. Di Santo, L. Scipione. New N,N-dimethylcarbamate inhibitors of acetylcholinesterase: design synthesis and biological evaluation. J. Enzyme Inhib. Med. Chem. 2016, 31, 106-113. DOI: 10.1080/14756366.2016.1220377. (IF15 = 3.428)

5. A. Corona, F. S. di Leva, G. Riguglioso, L. Pescatori, V. N. Madia, F. Subra, O. Delelis, F. Esposito, M. Cadeddu, R. Costi, S. Cosconati, E. Novellino, R. Di Santo, E. Tramontano. New insights into the interaction between pyrrolyl diketoacids and HIV-1 integrase active site and comparison with RNase H. Antiviral Res. 2016, 236-243. DOI: 10.1016/j.antiviral.2016.09.008

6. T. Schmid, J. S. Blees, M. M. Bajer, J. Wild, L. Pescatori, G. Cuzzucoli Crucitti, L. Scipione, R. Costi, C. J. Henrich, B. Brüne, N. H. Colburn, R. Di Santo. Diaryl disulfides as novel stabilizers of tumor suppressor Pdcd4. PloS ONE 2016, 11, e0151643. DOI: 10.1371/journal.pone.0151643

7. K. K. Das, N. Razzaghi-Asl, S. N. Tikare, R. Di Santo, R. Costi, A. Messore, L. Pescatori, G. Cuzzucoli Crucitti, J. G. Jargar, S. A. Dhundasi, L. Saso. Hypoglycemic activity of curcumin synthetic analogues in alloxan-induced diabetic rats. J. Enzyme Inhib. Med. Chem. 2016, 31, 99-105. DOI: 10.3109/14756366.2015.1004061 (IF15 = 3.428)

8. L. Pescatori, M. Métifiot, S. Chung, T. Masoaka, G. Cuzzucoli Crucitti, A. Messore, G. Pupo, V. N. Madia, F. Saccoliti, L. Scipione, S. Tortorella, F. S. Di Leva, S. Cosconati, L. Marinelli, E. Novellino, S. F. J. Le Grice, Y. Pommier, C. Marchand, R. Costi, R. Di Santo. N-Substituted quinolinonyl diketo acid derivative sas HIV integrase strand transfer inhibitors and their activity against RNase H function of reverse transcriptase. J. Med. Chem. 2015, 58, 4610-4623. DOI: 10.1021/acs.jmedchem.5b00159 (IF14 = 5.447)

9. G. Cuzzucoli Crucitti, L. Pescatori, A. Messore, V. N. Madia, G. Pupo, F. Saccoliti, L. Scipione, S. Tortorella, F. S. Di Leva, S. Cosconati, E. Novellino, Z. Debyser, F. Christ, R. Costi, R. Di Santo. Discovery of N-aryl-naphthylamines as in vitro inhibitors of the interaction between HIV integrase and the cofactor LEDGF/p75. Eur. J. Med. Chem. 2015, 101, 288-294. DOI: 10.1016/j.ejmech. 2015.06.036 (IF14 = 3.447)

10. L. Friggeri, D. De Vita, F. Pandolfi, S. Tortorella, R. Costi, R. Di Santo, L. Scipione. Design, synthesis and evaluation of 3,4-dihydroxybenzoic acid derivatives as antioxidants, bio-metal chelating agents and acetylcholinesterase inhibitors. J. Enzyme Inhib. Med. Chem. 2015, 30, 166-172. DOI: 10.3109/14756366.2013.866657. (IF15 = 3.428)

11. G. Cuzzucoli Crucitti, M. Métifiot, L. Pescatori, A. Messore, V. N. Madia, G. Pupo, F. Saccoliti, L. Scipione, S. Tortorella, F. Esposito, A. Corona, M. Cadeddu, C. Marchand, Y. Pommier, E. Tramontano, R. Costi, R. Di Santo. Structure-activity relationship of pyrrolyl diketo acid derivatives as dual inhibitors of HIV-1 integrase and reverse transcriptase ribonuclease H domain. J. Med. Chem. 2015, 58, 1915-1928. DOI: 10.1021/jm501799k (IF14 = 5.447)

12. M. D’Ascenzio, P. Chimenti, M. C. Gidaro, C. De Monte, D. De Vita, A. Granese, L. Scipione, R. Di Santo, G. Costa, S. Alcaro, M. Yáñez, S. Corradori (Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies.J. Enzyme Inhib. Med. Chem. 2015, 30, in stampa, DOI: 10.3109/14756366. 2014.987138 (IF14 = 2.332)

13. J. Van Soom, G. Cuzzucoli Crucitti, R. Gladysz, P. Van der Veken, R. Di Santo, I. Stuyver, V. Buck, A.-M. Lambeir, V. Magdolen, J. Joossens, K. Augustyns.The first potent diphenyl phosphonate K inhibitors with unexpected binding kinetics MedChemCom 2015, 6, 1954-1958. DOI: 10.1039/C5MD00288E (IF14 = 2.495)

14. Ilari A, Pescatori L, Di Santo R, Battistoni A, Ammendola S, Falconi M, Berlutti F, Valenti P, Chiancone E. Salmonella enterica serovar Typhimurium growth is inhibited by the concomitant binding of Zn(II) and a pyrrolyl-hydroxamate to ZnuA, the soluble component of the ZnuABC transporter. Biochim Biophys Acta. 2016, 1860, 534-541. DOI: 10.1016/j.bbagen.2015.12.006.

15. Schneider A, Corona A, Spöring I, Jordan M, Buchholz B, Maccioni E, Di Santo R, Bodem J, Tramontano E, Wöhrl BM.Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reversetranscriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors. Nucleic Acids Res. 2016, 44, 2310-22. DOI: 10.1093/nar/gkw060.

16.De Vita D, Moraca F, Zamperini C, Pandolfi F, Di Santo R, Matheeussen A, Maes L, Tortorella S, Scipione L. In vitro screening of 2-(1H-imidazol-1-yl)-1-phenylethanol derivatives as antiprotozoal agents and docking studies on Trypanosoma cruzi CYP51.Eur J Med Chem. 2016, 113, 28-33. DOI: 10.1016/j.ejmech.2016.02.028.

17. De Vita D, Pandolfi F, Cirilli R, Scipione L, Di Santo R, Friggeri L, Mori M, Fiorucci D, Maccari G, Arul Christopher RS, Zamperini C, Pau V, De Logu A, Tortorella S, Botta M.Discovery of in vitro antitubercular agents through in silico ligand-based approaches.Eur J Med Chem. 2016, 121, 169-80. DOI: 10.1016/j.ejmech.2016.05.032.