The NMTrypI concept is based on the development of innovative drug leads including a mechanism- based combination of a known and investigational drug and dual targets inhibition by using a common drug discovery platform. The platform is established by experts in their respective fields from SMEs and the public research sector in Europe and in disease-endemic countries.
The innovative concept is reinforced by the identification of preclinical biomarkers enabling the proteomic profiling of the compound to understand the mechanism of action (MoA biomarker) and to detect the efficacy of the lead candidate (pharmacodynamic biomarkers).
The new NMTrypI platform will perform the screening of compound libraries, lead development, testing in mice, hamsters and dogs as a reservoir of the visceral leishmaniasis disease as well as toxicology and safety testing (in vitro against cellular types and in vivo in animals) to overcome current limitations in anti-trypanosomatid therapy.
The major strength of the Consortium lies in the complementary partners' expertise and the integrated platform that will provide:
EXPECTED IMPACTS RELATED TO THE WORK PROGRAMME
The application of the new NMTrypI approach is expected to lead to an adapted and affordable treatment of Trypanosomatid Infections in disease endemic countries. The NMTrypI project may contribute to a major breakthrough towards finding a real therapy for NTDs.
Carrying out the project at international level with the inclusion of EU and disease-endemic countries in the consortium provide unique blend of experts to work in the field of trypanosomatidae which would further increase the versatility of the projects outcome.
The four intensive research SMEs involved in the project aim at exploiting the results generated in order to generate more revenues for the companies and therefore develop their competitiveness allowing them to gain new markers, to further develop their research and also to create more jobs.
ETHICAL ASPECTS OF NMTrypI PROJECT
The aim of the NMTrypI project is the discovery of potentially useful drugs for trypanosomatid diseases affecting humans and dogs for which no satisfactory treatment exists.
Research project involves the use of experimental animals, namely mice, hamsters and dogs. Experimental approach involves the use of in vitro primary screening with the aim of reducing the need of animal experimentation or at least reduces the numbers of animals needed.
However, selection of hits and leads by in vitro selection does not preclude the employment of limited numbers of animals as the final step of evaluation of the new treatments. Nonetheless, selection model employed has drastically reduced the need of experimental animals.
European regulation and international codes of conduct
The use of animals in NMTrypI research activities will take into account and strictly adhered to:
INTELLECTUAL PROPERTY (IP) COMMITTEE
The Intellectual Property (IP) Committee is composed of one IP expert from UNIMORE (M. P. Costi), one from SME (A. Venturelli, TYDOCK) and one from academic (T. Calogeropoulou, NHRF).
The IP Committee is a consulting body for IP topics to the project and consortium, and it has three main functions:
WP1: Lead optimization & synthesis. Predictive ADME-Tox evaluation.
The overall objective of WP1 is to generate lead compounds belonging to three compound classes:
i) Synthetic folate pathway-targeting pteridines, benzothiazole and thiadiazole derivatives.
ii) Improved miltefosine analogues and
iii) natural products.
WP1 leader: Dr. Theodora Calogeropoulou, NHRF
Main outcomes of WP1:
WP2: Studies on purified targets. M/HTS assays for Lead development.
WP2 integrates the screening of compound libraries. The target proteins will be obtained and inhibitor- target interaction studies will be performed using biophysical methods (x-ray crystallography, fluorescence spectroscopy, isothermal titration calorimetry).
The optimized leads will be identified through HTS target testing and combinations prioritized according to cellular liability assays results. In vitro toxicity, ADME and safety (in WP3) are prepared for delivery in animals (WP5).
WP2 leader: Dr. Theodora Calogeropoulou, NHRF
Main outcomes of WP2:
WP3: Phenotypic screening. M/HTS assays, ADME-Tox evaluation.
WP3 concerns the development of functional screening through cellular testing.
Natural compound mixtures are tested first on sensitive parasites and then the optimal mixture tested against relevant drug resistant strains. Only the selected mixtures from the dereplication process will be purified, and compound isolated and characterized. Final ranking and selection of the leads identified with related molecular and biological properties will be provided based on TDLP criteria.
Decisions on compounds progression towards WP3 and WP5 or feed-back to WP1 for further chemical modification will be taken
WP3 leader: Dr. Sheraz Gul, Fraunhofer IME-SP
Main outcomes of WP3:
WP4: Drug leads: mechanism of action, biomarkers, and resistance.
The aims of WP4 is to identify the mechanism of action and off-target effects for improving the design of optimized leads and to identify in vitro potential drug resistance that may evolve from the delivery of the leads to the parasites. Optimized drug leads designed on the basis of the off-targets are identified to be fed back to lead optimization in WP1. Combinations of PTR1 and DHFR inhibitors will be studied independently and then together, following the appropriate protocols.
Biomarkers (protein profile) through proteomic approach of drug lead action on parasites will be obtained. The evaluation of the efficacy of drug candidates in T. cruzi, T. brucei, L. major, L. infantum, L. donovani infections in animals to be performed in WP5.
WP4 leader: Dr. Joachim Clos, BNI
Main outcomes of WP4:
WP5: Animal models of candidate drug evaluation. PK, toxicity and safety studies.
WP5 aims at determining the efficacy of non-toxic and safe selected leads (WP2) against laboratory models of trypanosomatid infection (Trypanosoma spp, Leishmania spp).
Secondly, WP5 aims at evaluating the in vivo toxicity, safety, PK and PD parameters' of selected drugs in different organs from the mice & hamsters models.
Thirdly, WP5 aims at testing specificity and leishmanicidal activity in dog models for the most promising candidate drugs.
WP5 leader: Dr. Anabela Cordeiro-da-Silva, IBMC
Main outcomes of WP5:
WP6: Database design and data management.
The main objective of WP6 is to provide comprehensive data management for the project, i.e. a place to collect, structure and share data: experimental data, models, standard operating procedures (SOPs), as well as a participant directory (yellow pages).
WP6 leader: Dr. Wolfgang Mueller, HITS
Main outcomes of WP6:
WP7: Communication/Dissemination/Exploitation & International cooperation.
The main objective of WP7 are the following:
WP8: Project management.
The overall objective of this WP is to ensure the successful implementation of the NMTrypI project on the scientific, financial, and management levels.
The specific objectives are the following:
WP9: Synergic collaborative activities.
WP9 is dedicated to foster collaboration among the four projects on Neglected Parasitic Diseases financed under the EU call "FP7-HEALTH-2013-2-2-4-2 Drug development for NPD": NMTrypI, KINDReD, A-ParaDDisE and PDE4NPD.
The synergic activities aims at identifying a common platform for procedure standardization in particular for animal models evaluation.
For more information, see the "FP7-Projects - SYNERGY" page.
WP9 leader: Prof. Maria Paola Costi, UNIMORE