Goal: Research on Trypanosomatidic diseases is limited and fragmented, and funding initiatives are generally weak or lacking critical mass. Problems associated with existing drugs include inefficient delivery, insufficient efficacy, excessive toxicity and increasing resistance. New drugs are urgently needed now and in the near future. The New Medicines for Trypanosomatidic Infections - NMTrypI project aims at obtaining new candidate drugs against Trypanosomatidic infections with appropriate efficiency from the lead phase to the final preclinical phase that are more accessible to patients.
The exploitation of discoveries (target specific inhibitor/ compounds) will contribute to a reduction in the high socio-economic impacts of Leishmaniasis, Human African Trypanosomiasis and Chagas disease: it will improve the chances to identify new chemical entities for the development of innovative drugs. The NMTrypI project participates to the Data Sharing principle3 through the SEEK database4.
Project websites
https://fp7-nmtrypi.eu/index.html
All data from the studies are accessible after publication on a registration basis on the databse SEEK at the following address:
https://nmtrypi.h-its.org
Publications related to the NMTrypI project
Pasquale Linciano, Gregori Cullia, Chiara Borsari , Matteo Santucci, Stefania Ferrari, Gesa Witt, SherazGul, Maria Kuzikov, Bernhard Ellinger, Nuno Santarém, Anabela Cordeiro da Silva, Paola Conti, Maria Laura Bolognesi, Marinella Roberti, Federica Prati, Francesco Bartoccini Michele Retini, Giovanni Piersanti, Andrea Cavallie, Luca Goldoni, Sine Mandrup, Bertozzi Fabio Bertozzi, Enzo Brambilla, Vincenzo Rizzo, Daniele Piomelli, Andrea Pinto, Tiziano Bandiera, Maria Paola Costi. Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign. European Journal of Medicinal Chemistry. Available online 10 January 2020, 112047.doi.org/10.1016/j.ejmech.2020.112047
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Mª Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade and Maria Paola Costi*Hits and Lead discovery in the identification of new drugs against the trypanosomatidic infections. in “MEDICINAL CHEMISTRY OF NEGLECTED TROPICAL DISEASES. Advances in the design and synthesis of antimicrobial agents” to be published by CRC Press, Taylor & Francis Group. 2019.
Landi G, Linciano P, Borsari C, Bertolacini CP, Moraes CB, Cordeiro-da-Silva A, Gul S, Witt G, Kuzikov M, Costi MP, Pozzi C, Mangani S. Structural Insights into the Development of Cycloguanil Derivatives as Trypanosoma brucei Pteridine-Reductase-1 Inhibitors. ACS Infect Dis. 2019 May 1. doi:10.1021/acsinfecdis.8b00358. [Epub ahead of print] PubMed PMID: 31012301.
Borsari C, Santarem N, Macedo S, Jiménez-Antón MD, Torrado JJ, Olías-Molero AI, Corral MJ, Tait A, Ferrari S, Costantino L, Luciani R, Ponterini G, Gul S,Kuzikov M, Ellinger B, Behrens B, Reinshagen J, Alunda JM, Cordeiro-da-Silva A, Costi MP. SAR Studies and Biological Characterization of a Chromen-4-one Derivative as an Anti-Trypanosoma brucei Agent. ACS Med Chem Lett. 2019 Jan 29;10(4):528-533. doi: 10.1021/acsmedchemlett.8b00565. eCollection 2019 Apr 11.PubMed PMID: 30996791; PubMed Central PMCID: PMC6466517.
Linciano P, Pozzi C, Iacono LD, di Pisa F, Landi G, Bonucci A, Gul S, Kuzikov M, Ellinger B, Witt G, Santarem N, Baptista C, Franco C, Moraes CB, Müller W, Wittig U, Luciani R, Sesenna A, Quotadamo A, Ferrari S, Pöhner I, Cordeiro-da-Silva A, Mangani S, Costantino L, Costi MP. Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections. J Med Chem. 2019 Apr 25;62(8):3989-4012. doi:10.1021/acs.jmedchem.8b02021. Epub 2019 Apr 9. PubMed PMID: 30908048.
Vanossi D, Caselli M, Pavesi G, Borsari C, Linciano P, Costi MP, Ponterini G. Excited-state intramolecular proton transfer in a bioactive flavonoid provides fluorescence observables for recognizing its engagement with target proteins. Photochem Photobiol Sci. 2019 Mar 22. doi: 10.1039/c9pp00026g. [Epub ahead of print] PubMed PMID: 30900698.
Moraes CB, Witt G, Kuzikov M, Ellinger B, Calogeropoulou T, Prousis KC, Mangani S, Di Pisa F, Landi G, Iacono LD, Pozzi C, Freitas-Junior LH, Dos Santos Pascoalino B, Bertolacini CP, Behrens B, Keminer O, Leu J, Wolf M, Reinshagen J, Cordeiro-da-Silva A, Santarem N, Venturelli A, Wrigley S, Karunakaran D, Kebede B, Pöhner I, Müller W, Panecka-Hofman J, Wade RC, Fenske M, Clos J, Alunda JM, Corral MJ, Uliassi E, Bolognesi ML, Linciano P, Quotadamo A, Ferrari S, Santucci M, Borsari C, Costi MP, Gul S. Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform. SLAS Discov. 2019 Mar;24(3):346-361. doi:10.1177/2472555218823171. PubMed PMID: 30784368.
Chiara Borsari, Antonio Quotadamo, Stefania Ferrari, Alberto Venturelli, Anabela Cordeiro-da-Silva, Nuno Santarem,Maria Paola Costi. Scaffolds and Biological Targets Avenue to Fight Against Drug Resistance in Leishmaniasis. Annual Reports In Medicinal Chemistry: Medicinal Chemistry Approaches To Overcome Antibiotics Resistance volume 51, 2018.
Jiménez-Antón MD, García-Calvo E, Gutiérrez C, Escribano MD, Kayali N, Luque-García JL, Olías-Molero AI, Corral MJ, Costi MP, Torrado JJ, Alunda JM. Pharmacokinetics and disposition of miltefosine in healthy mice and hamsters experimentally infected with Leishmania infantum. Eur J Pharm Sci. 2018 Aug 30;121:281-286. doi: 10.1016/j.ejps.2018.06.002. Epub 2018 Jun 5. PubMed PMID: 29883726.
Uliassi E, Piazzi L, Belluti F, Mazzanti A, Kaiser M, Brun R, Moraes CB, Freitas-Junior LH, Gul S, Kuzikov M, Ellinger B, Borsari C, Costi MP, Bolognesi ML. Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections. ChemMedChem. 2018 Apr 6;13(7):678-683. doi: 10.1002/cmdc.201700786. Epub 2018 Feb 16. PubMed PMID:29451361.
Linciano P, Moraes CB, Alcantara LM, Franco CH, Pascoalino B, Freitas-Junior LH, Macedo S, Santarem N, Cordeiro-da-Silva A, Gul S, Witt G, Kuzikov M, Ellinger B, Ferrari S, Luciani R, Quotadamo A, Costantino L, Costi MP. Aryl thiosemicarbazones for the treatment of trypanosomatidic infections. Eur J Med Chem. 2018 Feb 25;146:423-434. doi: 10.1016/j.ejmech.2018.01.043. Epub 2018 Jan 31. PubMed PMID: 29407968.
Herrmann FC, Sivakumar N, Jose J, Costi MP, Pozzi C, Schmidt TJ. In Silico Identification and In Vitro Evaluation of Natural Inhibitors of Leishmania major Pteridine Reductase I. Molecules. 2017 Dec 6;22(12). pii: E2166. doi:10.3390/molecules22122166. PubMed PMID: 29211037; PubMed Central PMCID:PMC6149668.
Uliassi E, Fiorani G, Krauth-Siegel RL, Bergamini C, Fato R, Bianchini G, Carlos Menéndez J, Molina MT, López-Montero E, Falchi F, Cavalli A, Gul S, Kuzikov M, Ellinger B, Witt G, Moraes CB, Freitas-Junior LH, Borsari C, Costi MP, Bolognesi ML. Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display trypanocidal activity. Eur J Med Chem. 2017 Dec 1;141:138-148. doi: 10.1016/j.ejmech.2017.10.005. Epub 2017 Oct 3. PubMed PMID: 29031061.
Linciano P, Dawson A, Pöhner I, Costa DM, Sá MS, Cordeiro-da-Silva A, Luciani R, Gul S, Witt G, Ellinger B, Kuzikov M, Gribbon P, Reinshagen J, Wolf M, Behrens B, Hannaert V, Michels PAM, Nerini E, Pozzi C, di Pisa F, Landi G, Santarem N, Ferrari S, Saxena P Lazzari S, Cannazza G, Freitas-Junior LH, Moraes CB, Pascoalino BS, Alcântara LM, Bertolacini CP, Fontana V, Wittig U, Müller W, Wade RC, Hunter WN, Mangani S, Costantino L, Costi MP. Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery. ACS Omega. 2017 Sep 30;2(9):5666-5683. doi: 10.1021/acsomega.7b00473. Epub 2017 Sep 11. PubMed PMID: 28983525; PubMed Central PMCID: PMC5623949
Panecka-Hofman J, Pöhner I, Spyrakis F, Zeppelin T, Di Pisa F, Dello Iacono L, Bonucci A, Quotadamo A, Venturelli A, Mangani S, Costi MP, Wade RC. Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors. Biochim Biophys Acta Gen Subj. 2017 Dec;1861(12):3215-3230. doi: 10.1016/j.bbagen.2017.09.012. Epub 2017 Sep 20. PubMed PMID: 28939533.
Pierce RJ, MacDougall J, Leurs R, Costi MP. The Future of Drug Development for Neglected Tropical Diseases: How the European Commission Can Continue to Make a Difference. Trends Parasitol. 2017 Aug;33(8):581-583. doi: 10.1016/j.pt.2017.04.007. Epub 2017 May 18. PubMed PMID: 28529130.
Di Pisa F, Landi G, Dello Iacono L, Pozzi C, Borsari C, Ferrari S, Santucci M, Santarem N, Cordeiro-da-Silva A, Moraes CB, Alcantara LM, Fontana V, Freitas-Junior LH, Gul S, Kuzikov M, Behrens B, Pöhner I, Wade RC, Costi MP, Mangani S. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity. Molecules. 2017 Mar 8;22(3). pii: E426. doi:10.3390/molecules22030426. PubMed PMID: 28282886; PubMed Central PMCID: PMC6155272.
Bruno S, Uliassi E, Zaffagnini M, Prati F, Bergamini C, Amorati R, Paredi G, Margiotta M, Conti P, Costi MP, Kaiser M, Cavalli A, Fato R, Bolognesi ML.Molecular basis for covalent inhibition of glyceraldehyde-3-phosphate dehydrogenase by a 2-phenoxy-1,4-naphthoquinone small molecule. Chem Biol Drug Des. 2017 Aug;90(2):225-235. doi: 10.1111/cbdd.12941. Epub 2017 Mar 6. PubMed PMID: 28079302.
Borsari C, Santarem N, Torrado J, Olías AI, Corral MJ, Baptista C, Gul S, Wolf M, Kuzikov M, Ellinger B, Witt G, Gribbon P, Reinshagen J, Linciano P, Tait A, Costantino L, Freitas-Junior LH, Moraes CB, Bruno Dos Santos P, Alcântara LM, Franco CH, Bertolacini CD, Fontana V, Tejera Nevado P, Clos J, Alunda JM, Cordeiro-da-Silva A, Ferrari S, Costi MP. Methoxylated 2'-hydroxychalcones as antiparasitic hit compounds. Eur J Med Chem. 2017 Jan 27;126:1129-1135. doi:10.1016/j.ejmech.2016.12.017. Epub 2016 Dec 9. PubMed PMID: 28064141.
Borsari C, Luciani R, Pozzi C, Poehner I, Henrich S, Trande M, Cordeiro-da-Silva A, Santarem N, Baptista C, Tait A, Di Pisa F, Dello Iacono L, Landi G, Gul S, Wolf M, Kuzikov M, Ellinger B, Reinshagen J, Witt G, Gribbon P, Kohler M, Keminer O, Behrens B, Costantino L, Tejera Nevado P, Bifeld E, Eick J, Clos J, Torrado J, Jiménez-Antón MD, Corral MJ, Alunda JM, Pellati F, Wade RC, Ferrari S, Mangani S, Costi MP. Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs. J Med Chem. 2016 Aug 25;59(16):7598-616. doi: 10.1021/acs.jmedchem.6b00698. Epub 2016 Aug 5. PubMed PMID: 27411733.
Gaspar L, Moraes CB, Freitas-Junior LH, Ferrari S, Costantino L, Costi MP, Coron RP, Smith TK, Siqueira-Neto JL, McKerrow JH, Cordeiro-da-Silva A. Current and Future Chemotherapy for Chagas Disease. Curr Med Chem. 2015;22(37):4293-312. Review. PubMed PMID: 26477622.