Pain Project (PDCT/SAU-FCF/69493/2006)
Kyotorphin (KTP) is an analgesic molecule first isolated from bovine brain by Japanese researchers working in Kyoto, in 1979 . Although its activity is 4-fold higher relative to endogenous opioids , it is effective only if applied directly in the brain. This limitation prevents its pharmacological application.
Researchers from Portugal (Schools of Medicine of the University of Lisbon, Institute of Molecular Medicine, and University of Porto) and Spain (University of Girona) conceived and synthesized a derivative of KTP (KTP-RC), modified in a way to make it effective after administration in blood. This efficacy was proven in vivo. This seminal work was funded by the Portuguese Foundation for Science and Technology (Project code PDCT/SAU-FCF/69493/2006).
Yet, to turn KTP-RC into a safe drug that can be used by patients, KTP-RC has to go through further tests, eventualy new modifications, and enroll a programme of technological development. Three other teams joined efforts with the Universities of Lisbon, Porto and Girona to tackle these needs: the University of Tübingen and Synovo (both from Germany) and Bioalvo (Portugal). Toghether, they formed a consortium that applied to funding from the IAPP (Industry-Academia Partnerships and Pathways) Marie Curie Actions, under the 7th Framework Programme. The project was considered of high quality and funded. It started in March 2010 and new derivatives of KTP have been identified and very favorable toxicity profiles were detected.
FP7 Project - Pep2Brain
BLV200703/4 (amidated kyotorphin) is a small molecule discovered jointly by groups from the University of Lisbon (Portugal) and Girona (Spain) that proved its efficacy in analgesia from behavioural tests in rats. The same molecule was tested in a platform that screens potential pharmacological molecules/compounds for neurodegenerative diseases with positive results. The platform is owned by Bioalvo, SA (Portugal). The preliminary results obtained regarding efficacy and toxicology of the molecule were encouraging and the academic inventors and the industrial developers have joined efforts.
A starting phase of lead optimisation was followed, by combining in vitro and in vivo assays, in order to achieve the best pharmacological and ADME/toxicity characteristics. This required technology, knowledge and innovation transfer since the inventors and Bioalvo were unable to perform this endeavour on their own. Synovo, a German company expert in ADME/tox tests and the University of Tuebingen, with a group expert in Medicinal Chemistry, joined Bioalvo and the Universities of Lisbon and Girona to transfer all knowledge, technology and innovation necessary to make possible that BLV200703/04 or one of its future derivatives reaches pre-clinical stage.
During the project new variants of the peptide drug lead were synthesised and then tested in vitro and in vivo for stability, safety and efficacy. Several approaches were considered in the design of such derivatives, namely, the innovative covalent combination with Ibuprofen, one of the safest NSAIDs (non-steroid anti-inflammatory drug).
Overall, our data show enhanced brain targeting and analgesia in the absence of significant toxicity or the side-effects usually associated with opioids, which makes these new molecules extremely promising compounds for future pharmaceutical development.
Project Acronym: PEP2BRAIN
Contract Type: Industry-Academia Partnerships and Pathways (IAPP), Grant Agreement Nº 230654
Duration: 2009-03-01 to 2013-02-28 (total: 48 months)