Salford science
Author: Prathyusha Viswanathan (University of Salford)
Keywords:
How to Cite: Viswanathan, P. (2023) “Fast-tracking anti-malarial drug discovery through re-positioning”, BioScientist: The Salford Biomedicine Society Magazine. 1(3). doi: https://doi.org/10.57898/biosci.166
Malaria is one of the oldest diseases known to mankind and among one of the top three infectious killer diseases 1 . It is caused by a parasite genus known as Plasmodium. Over the years, scientists have developed many drugs to treat the disease, but “drug resistance” is known to affect all well-known categories of anti-malarial drugs including the front-line artemisinins 2 . Unfortunately, the traditional discovery pipeline to develop new drugs could take about 15-17 years 3 .
Prof. Niroshini Nirmalan, Head of Biomedicine at the University of Salford, leads the Malaria research group which has been conducting research aiming to find a fast-tracked solution for malaria via ‘re-positioning’ of drugs which involves identifying new therapeutic drugs by modifying existing drugs 4 . We have interviewed her about her research below.
We are focusing only on Plasmodium falciparum because it causes the deadliest version of malaria. It is the only species that causes cerebral malaria, which accounts for most of the deaths globally. The main aspect of this research is to use drug re-positioning to fast-track drug discovery. It is the re-positioning of existing FDA approved drugs in diseases other than those it was originally invented for. We began this research 8 years ago and have had several PhD and MRes students involved in different aspects of the project.
Initially, we screened 1250 FDA approved drugs on in-vitro P. falciparum t o identify approximately 50 drugs repositioning in Malaria. As we went further, one plant derived anti-amoebic drug named Emetine dihydrochloride seemed to be impressive in our screens as a viable option for repositioning in Malaria. Since then, we have been focusing on re-positioning and developing the compound and its analogues as a potential drug to fight against P. falciparum.
This research contains very specialized cultures. We culture the parasites in human blood and monitor the parasite life cycles in the red cells that repeats itself. Other specialized techniques include in vitro antimalarial drug screening, Calcusyn drug synergy analysis, in-silico modelling, lead optimization and analogue synthesis and natural product drug discovery methods.
No, not yet. I suppose we were one of the first research groups to apply this technique to fast-track drug discovery in malaria.
Oh yes, initially when I asked many researchers about Emetine, they asked me not to touch it and said it was a poison. But my memory was good, and I remembered that it was widely used to treat amoebic dysentery and hepatic abscesses in South East countries like India & Srilanka . So, I decided to perform a little bit of research to check this. We resynthesized emetine analogs with better safety profiles and modelled it. Our work showed that the doses of emetine required for malaria was a thousand-fold less than the effective dose for amoebiasis. We know that the side effects are dose dependent, and we now have evidence to hypothesize that the component is not harmful when used in proper doses.
Another most important bit that will surprise you is, we have discovered that we would require only an extremely tiny quantities of emetine to treat P. falciparum as in nanomolar concentration to be precise. Our work is constantly expressed on the public domain. Initially we made our first publications in 2014 and were considered as one of the first ever drug repositioning papers in malaria. We have also published various journals over all these years in regards to our research. Our most recent publications in 2020, was a very high-profile paper on a synthetic derivative of emetine called Dehydroemetine. Recently, many researchers have acknowledged our work, appreciated it and have started to perform various tests using this compound.
Those side effects caused by emetine are all dosage based and can be controlled. In Malaria, since the usage is in extremely lower concentrations, we can strongly argue that the side effects will be minimal in most cases. However, we are yet to study this in a very detailed manner.
Oh yes, there were several leads like that. As I said, initially we screened 50 drugs. These 50 drugs showed positive results at first, but as we proceeded further, we encountered some errors and while we investigated them, we found them either to be not effective or only effective in extremely high doses. So yes, there were many times we had taken up the leads and we had to do so much to go beyond that point and get back on track.
It looks like an early acting drug. We can see activity in 24 hours.
Yes, it is most likely to be effective is P. vivax as well. All current antimalarials are active against both strains. So, the same is likely to be seen with emetine which is currently effective at low nanomolar concentrations.
Recently, we carried our project on to the next level and performed a preliminary animal work on mice – and I must say it is very promising!
Regarding Emetine, the next phase would be performing animal trials on a larger scale followed by safety trials. On the other hand, apart from Emetine, we have also started to look out for many other natural products like mushrooms, some native African plants etc as sources of future drugs and we have got quite a few interesting data coming up from that as well.
1. WHO. Malaria. Published 2021. Accessed April 4, 2021. https://www.who.int/news-room/fact-sheets/detail/malaria
2. Phyo AP, Win KK, Thu AM, et al. Poor response to artesunate treatment in two patients with severe malaria on the Thai–Myanmar border. Malar J . 2018;17(1):30. doi:10.1186/s12936-018-2182-z
3. Drug Discovery and Development. Basic Clin Pharmacol Toxicol . 2014;115:92-161. doi:10.1111/bcpt.12259_3
4. Persaud-Sharma V, Zhou S-F. Drug Repositioning: A Faster Path to Drug Discovery. Adv Pharmacoepidemiol Drug Saf . 2012;01(06). doi:10.4172/2167-1052.1000e117
Matthews H, Deakin J, Rajab M, Idris-Usman M, Nirmalan NJ. Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. Bogyo M, ed. PLoS One . 2017;12(3):e0173303. doi:10.1371/journal.pone.0173303
Matthews H, Usman-Idris M, Khan F, Read M, Nirmalan N. Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate. Malar J . 2013;12(1):359. doi:10.1186/1475-2875-12-359
Panwar P, Burusco KK, Abubaker M, et al. Lead Optimization of Dehydroemetine for Repositioned Use in Malaria. Antimicrob Agents Chemother . 2020;64(4). doi:10.1128/AAC.01444-19