Though less lively than their cartoon counterpart, deep-ocean sponges are helping researchers alleviate symptoms of Down syndrome, Alzheimer’s disease and dementia. Research spearheaded by the Perha Pharmaceuticals lab in Roscoff, France, has produced a promising drug candidate, Leucettinib-21. I had the opportunity to meet the lead researcher, Dr Laurent Meijer, and ask him about the process of finding a possible candidate molecule from the wild and all the steps involved between the discovery and development of a functioning drug product. By Martin Gazancon
Dr Laurent Meijer and his team have been working on a protein kinase inhibitor as a candidate drug. Physiologically, kinases are crucial because they modulate the behaviour of target proteins via the addition of phosphate groups (phosphorylation). Through phosphorylation, kinases can mediate essential regulatory and signalling mechanisms. However, like most biological processes, abnormal levels of phosphorylation can have severe consequences, leading to various pathologies. As a result, kinase inhibitors, which prevent target protein phosphorylation, are a significant research focus in the drug development sector.
Recent research from the Meijer lab has focused on 2 kinase subtypes: dual-specificity tyrosine phosphorylation-activated kinases (DYRKs) and cdc2-like kinases (CLKs); with particular attention paid to DYRK1A, which has been implicated in both Down syndrome and Alzheimer's disease (Arbones et al., 2019). Firstly, this is due to the DYRK1A gene being located in the Down syndrome critical region of the chromosome, which, when triplicated, causes Down syndrome. The other reason is DYRK1A's role in phosphorylating key Alzheimer's disease regulators. DYRK1A inhibition offered a promising opportunity to not only treat Alzheimer's disease but also Down syndrome; therefore, screening for a DYRK1A inhibitor was initiated by the research group (Stotani et al., 2016).
Figure 1: A schematic showing the multi-phase screening process for a DYRK1A inhibitor, Leucettinib-21. Firstly, a drug candidate, Leucettamine B, is selected from an initial library of compounds (cpds), then through different point mutations (medical chemistry) Leucettamine B is altered to create a product family, Leucettines; the best is selected by several criteria including potency, selectivity and toxicity. This process repeats until we are left with the primary drug candidate, Leucettinib-21 which then undergoes preclinical studies including animal testing. Abbreviations: Compounds (cpds), Proof of concept (PoC); Clinical Trial Application (CTA).
[Reproduced image from source: Laurent Meijer, Perha Pharmaceuticals website, accessed 20 October 2024, https://www.perha-pharma.com/pipeline]
The initial phase of screening involved creating a product family called the Leucettines – a class of DYRK/CLK kinase inhibitors inspired by the Leucettamine B, a product of the marine sponge Leucetta microraphis. Out of the 500 analogues synthesised, Leucettine L-41 treated cognitive deficits but had several defects, such as low efficacy and affinity, making it unsuitable as a drug candidate. Therefore, a new family, Leucettinibs, was synthesised from the Leucettines. Extensive screening of over 670 analogues then identified Leucettinib-21 as the most effective and was therefore chosen as the primary drug candidate (Lindberg et al., 2023). With pre-clinical trials completed, what is the next step? Clinical trials to determine Leucettinib-21’s efficacy and safety in humans (Branca et al., 2017).
Currently, the lab is progressing through phase 1 clinical trials, performed on healthy adult volunteers. These phase 1 tests will last until the end of 2024 and involve a series of assessments, such as single and multiple ascending doses, followed by tests on adult patients with Alzheimer’s disease and Down syndrome. Once completed, phase 2 tests will begin, examining the drug’s effects on affected children. Extensive testing before commercialising is essential to ensure Leucettinib-21 will function appropriately under various pharmacological conditions and patient types (Lindberg et al., 2023).
Taking a step back, we must consider dementia. Despite sounding familiar, many don’t know what it entails (including myself, before researching). Dementia is an umbrella term for various diseases affecting cognitive ability, including memory and motor function. Worldwide, dementia has been classified as one of the leading causes of death by the World Health Organisation, with an estimated 55 million individuals currently affected and a projected 10 million new cases each year. Of all the causes of the condition, Alzheimer’s disease has accounted for nearly 70% of these cases and is, therefore, an important application for drugs like Leucettinib-21.
If Leucettinib-21 performs well during the phase 2 and phase 3 clinical trials and receives approval from the ANSM (Agence National de Sécurité du Medicament) - the French equivalent to the US FDA (Food and Drug Administration) - it could help alleviate symptoms for millions of patients affected by Down syndrome, Alzheimer’s disease and dementia. Perha Pharmaceuticals’ research not only highlights the importance of clinical research to s previously untreatable diseases but also the power of creativity, as all of this research stemmed from a simple sponge under the sea.
References
Cover Image: Pexels; https://www.pexels.com/photo/spongebob-squarepants-28065063/
Arbones ML, Thomazeau A, Nakano-Kobayashi A, Hagiwara M, Delabar JM. DYRK1A and cognition: A lifelong relationship. Pharmacol Ther. 2019 Feb;194:199–221.
Branca C, Shaw DM, Belfiore R, Gokhale V, Shaw AY, Foley C, et al. Dyrk1 inhibition improves Alzheimer’s disease-like pathology. Aging Cell. 2017 Oct;16(5):1146–54.
Lindberg MF, Deau E, Arfwedson J, George N, George P, Alfonso P, et al. Comparative Efficacy and Selectivity of Pharmacological Inhibitors of DYRK and CLK Protein Kinases. J Med Chem. 2023 Mar 23;66(6):4106–30.
Stotani S, Giordanetto F, Medda F. DYRK1A inhibition as potential treatment for Alzheimer’s disease. Future Med Chem. 2016 Apr;8(6):681–96.
