ICF: Lead Optimisation of a Series of Antimalarial Plasmepsin IX/X Beta-hydroxyethylamine Based Inhibitors
Lead Research Organisation:
University of Liverpool
Department Name: Chemistry
Abstract
Although there have been positive advances in the treatment of malaria, it remains a serious threat to global health, with 619,000 fatalities occurring worldwide (>90% in Africa) in 2021. These facts, combined with a threat of extended geographical malaria transmission due to climate change and increasing parasitic resistance towards available drugs , underline the importance in discovering new anti-malarial therapeutics with novel modes of action. In addition to drug resistance, significant drug attrition in the discovery phases of antimalarial drug development has occurred within the Medicines for Malaria Venture (MMV)'s portfolio over the last 5 years. (MMV is a not-for-profit public-private partnership, founded in 1999, with the mission to reduce the burden of malaria by the development of novel antimalarial drugs.)
Malaria is a disease that is transmitted by the bite of the female Anopheles mosquito and is caused by a parasite belonging to Plasmodium genus. One of the challenges in drug treatment of this parasite is its complex life cycle which involves development in the mosquito, and two separate stages of development within the liver and red blood cells of the human host. Finding drug molecules that can target the parasite at all three development stages is the holy grail of antimalarial drug discovery since this will enable an highly effective antimalarial "triple-hit" to be exerted.
Recently, two enzymes have been characterised known as Plasmepsins IX and X. These enzymes have been shown to be key to the parasite development in mosquito, blood and liver stages; inhibition of these proteins not only prevents the parasite invading human red blood cells but inhibition of plasmepsin X prevents the parasite from escaping the human red blood cell to continue the infection cycle. Recently, a breakthrough was made that showed a class of drug known as a protease inhibitor can inhibit these enzymes. This class of drug, which are chemically related to the HIV protease inhibitor drugs used for over two decades, have excellent parasite killing activity in test-tube experiments in the laboratory. More recently, one of these prototype drugs was shown to cure mice infected with Plasmodium species demonstrating the potential for development of an oral treatment of malaria infected human patients.
Given the broad acting nature of these new parasite inhibitors, medicinal chemists have the opportunity to develop a novel drug with potential for malaria treatment, mosquito transmission blocking and for prevention (also known as chemoprophylaxis). A molecule with such properties would be highly valuable in the clinic. The aim of the research is to improve the prototype inhibitor by chemical modification of the scaffold to increase parasite killing activity as well as increasing drug stability within the human body. Ideally the drug treatment should be capable of curing malaria in a single or three daily doses treatment regimen.
The project will use computational modelling, chemical synthesis and biological screening, as well as measurement and modelling of the metabolism of modified drugs to predict the drug exposures in humans. The aim is to obtain a molecule for preclinical profiling en route to a clinical trial in human inside 5 years. The programme is a multinational programme involving researchers in the UK (University of Liverpool, Imperial College, Liverpool School of Tropical Medicine), Italy (University of Milan) and Switzerland (MMV, University of Geneva).
Malaria is a disease that is transmitted by the bite of the female Anopheles mosquito and is caused by a parasite belonging to Plasmodium genus. One of the challenges in drug treatment of this parasite is its complex life cycle which involves development in the mosquito, and two separate stages of development within the liver and red blood cells of the human host. Finding drug molecules that can target the parasite at all three development stages is the holy grail of antimalarial drug discovery since this will enable an highly effective antimalarial "triple-hit" to be exerted.
Recently, two enzymes have been characterised known as Plasmepsins IX and X. These enzymes have been shown to be key to the parasite development in mosquito, blood and liver stages; inhibition of these proteins not only prevents the parasite invading human red blood cells but inhibition of plasmepsin X prevents the parasite from escaping the human red blood cell to continue the infection cycle. Recently, a breakthrough was made that showed a class of drug known as a protease inhibitor can inhibit these enzymes. This class of drug, which are chemically related to the HIV protease inhibitor drugs used for over two decades, have excellent parasite killing activity in test-tube experiments in the laboratory. More recently, one of these prototype drugs was shown to cure mice infected with Plasmodium species demonstrating the potential for development of an oral treatment of malaria infected human patients.
Given the broad acting nature of these new parasite inhibitors, medicinal chemists have the opportunity to develop a novel drug with potential for malaria treatment, mosquito transmission blocking and for prevention (also known as chemoprophylaxis). A molecule with such properties would be highly valuable in the clinic. The aim of the research is to improve the prototype inhibitor by chemical modification of the scaffold to increase parasite killing activity as well as increasing drug stability within the human body. Ideally the drug treatment should be capable of curing malaria in a single or three daily doses treatment regimen.
The project will use computational modelling, chemical synthesis and biological screening, as well as measurement and modelling of the metabolism of modified drugs to predict the drug exposures in humans. The aim is to obtain a molecule for preclinical profiling en route to a clinical trial in human inside 5 years. The programme is a multinational programme involving researchers in the UK (University of Liverpool, Imperial College, Liverpool School of Tropical Medicine), Italy (University of Milan) and Switzerland (MMV, University of Geneva).
Technical Summary
Malaria remains a serious threat to global health, with 619,000 fatalities in 2021. Our aim is to generate a new drug against uncomplicated malaria that is able to mitigate against the shortcomings of current therapies. The primary target of this programme is Plasmepsin X (with potential additional drug activity on the related Plasmepsin IX). Both of these aspartic acid protease enzymes are required for malaria parasite invasion with our primary target also critical for egress from the infected erythrocyte. These proteases are excellent targets for antimalarial drug development since in vitro and in vivo experiments have revealed specific inhibitors block liver, blood and mosquito stage development of Plasmodium spp. These properties provide a multi-stage inhibitory activity coupled with a unique mechanism of inhibition that has a high barrier to resistance development making Plasmepsin IX/X inhibitors attractive targets for drug development. We have already identified beta-hydroxyethylamine inhibitors with exceptional enzymatic and antimalarial potency (<1 pM) in vitro and have identified medicinal chemistry strategies that will deliver a late lead for progression into an effective oral treatment for malaria. A key goal of this project is to optimise the metabolic stability characteristics of our series to provide a late lead molecule. In this project we will: 1) produce a focused array of analogues of current frontrunners, 2) run in vitro SAR analyses and confirm improved physicochemical and in vitro pharmacokinetic characteristics and 3) evaluate the most promising leads with in vivo screens (Pf SCID mouse model) and de-risk them using PK studies and associated modelling along with in vitro toxicology experiments. Success in this milestone driven programme will allow late lead selection with the Medicines for Malaria Venture (MMV), with the aim of developing a drug that matches their primary candidate profile (TCP-1) along with secondary target product profiles.
