Research Groups‎ > ‎

RDS Drug Design & Development (CHIM/08)

Head of Laboratory: Di Santo Roberto, Roberta Costi
Sito web

Main Topics: 

The activity is focused on drug design and discovery (DDD). Main reseraches in the field of antimicrobial agents. In particular, discovery of new class of zinc chelators as inhibitors of ZnuABC transporter that has important role in the pathogenicity of Gram-negative bacteria. Moreover in the field of antiviral agents (discovery of novel classes of HIV NNRTI classes: AThPs, IN inhibitors, polyhydroxylated aromatics and diketoacids including quinolinones; inhibitors of RdRp of HCV), antifungal agents (analogues of bifonazole, ketoconazole and miconazole), antitumor agents (inhibitors of mammalian terminal transferases), and CNS agents (MAO inhibitors; anti-Alzheimer agents), and heterocyclic chemistry (pyrrole, indole, tri- and tetracylcic systems). Since 1996 studied HIV-1 integrase inhibitors as antiretroviral agents obtaining polyhydroxylated derivatives and aryldiketoacids endowed of potent antiviral activities. Also inhibitors of RNase H function of the reverse trascriptase enzyme of HIV were developed. Futher studies were devote to the discovery of inhibitors of viral (HCV RdRp, HIV- 1 RT) and human (TdT, pol λ) polymerases. Finally, he developed a novel approach to antitumor and antiviral chemotherapy with the discovery of novel modulators of chromatin remodeling (HAT inhibitors). Cooperating with Companies to develop anti-Alzheimer, antimalarial agents and ligands of 5-HT4 receptors.

National and International Collaborations:

International collaborations: National Institute of Health, Bethesda, USA (Prof. Yves Pommier), National Institute of Health, Frederick, USA (Prof. Stuart Le Grice), Katholieke Universiteit Leuven, Belgium (Jan Balzarini, Zeger Debyser, Christophe Pannecouque), Technical University of Lodz, Poland (Grzegorz Bujacz), Swiss Tropical Institute, Basel, Svizzera (Dott. Reto Brun), PET-center Arhus University Hospital, Arhus, Danimarca (Dr. Svend Borup Jensen), Max-Planck-Institut, Dortmund, Germania (Prof. Herbert Waldmann), Centre d’Etudes et de Recherche sur le Médicament de Normandie, Caen, Francia (Prof Sylvain Rault), Università della California, La Jolla, San Diego, USA (Prof. Aleem Siddiqui), Washington University, USA (Prof. Michael Gelb).

Facilities:

FT-IR (Perkin-Elmer)
HPLC (Shimadzu)
Mass Spectrometer (Thermo) – HPLC-MS


ERC Panels:

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

Grants (2015-2018):


1) COMBINED HIGHLY ACTIVE ANTI-RETROVIRAL MICROBICIDES 242135 (CHAARM). FP7-HEALTH 2009.European Microbicides Development Programme to 30-06-2015
2) "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
3) “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
4) Istituto Pasteur Cenci-Bolognetti (2014-17)“Dual IN and RNase H inhibitors to defeat HIV”. from 01-01-2014 to 01-01-2017
5) “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
6) 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

Laboratory members:

MADIA Valentina Noemi
MESSORE Antonella
SACCOLITI Francesco
TUDINO Valeria

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.