Introduction and Background of the Project

Introduction

Plasmodium cytoplasmic Prolyl-tRNA synthetase (PfProRS) is an enzyme essential for protein synthesis and is a clinically validated target for malaria (https://pubmed.ncbi.nlm.nih.gov/15422372/). Takeda and MMV have collaborated on a project targeting ProRS since April 2019 and have published preliminary work on a new chemical series https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00020).

Potent ATP-competitive pyridylpyrrolidone inhibitors of PfProRS have been identified with high selectivity over the human enzyme and also against human kinases. Compounds from the series also have high potency against clinical isolates of falciparum and vivax blood stages and also liver stages and there is an acceptable resistance profile.

The Early Lead MMV1902882 has good biochemical selectivity (Pf/Hs: 0.019uM/1.76uM) and high cellular selectivity (3D7 LDH/HepG2: 0.07uM/22uM). However, the potency, hERG inhibition (1.1uM, Q-patch) and low absorption (F=22% in mouse, MDR <2nm/sec) are key issues to be addressed by lead optimisation.

Project objective

The ultimate objective of this drug discovery collaboration is to deliver a Preclinical Candidate which targets Plasmodium ProRS and meets MMV’s candidate criteria for either prophylaxis (TCP-4) or treatment (TCP-1) shown here; https://www.mmv.org/frontrunner-templates. The objective of this two-year proposal is to initiate optimization of the lead pyridylpyrrolidones series to deliver a Late Lead which meets MMV’s criteria for prophylaxis (TCP-4) and is endorsed by MMV ESAC for entry into candidate profiling studies. The Late Lead could be potentially considered for treatment (TCP-1) if the resistance profile of the late lead improves. In more detail the objectives of the lead optimization project aim to achieve:

1. Increased parasite potency (i.e. 3D7 EC50 < 10nM)

2. Improving the predicted pharmacokinetics in human (according to MMVSola) such that the series is on track to deliver a late lead which meets the dose criteria for prophylaxis, i.e. a single dose MIC for 7d (minimum) or a single dose MIC for 28d (ideal).

3. Addressing the hERG inhibition

4. Confirming selectivity for Pf versus Hu ProRS >1000-fold according to appropriate functional biochemical and cellular assays

5. Determination of the parasitological profile, including rate of kill, potency against lab and clinical strains, efficacy in the SCID model, determination of resistance risk (MIR) etc.

6. Identification and mitigation of additional developability and safety risks; Ames, CYP inhibition, CMC.

Project design

A multi-disciplinary drug discovery approach will be used by the project, utilizing the inputs and diverse skills of the project team which has expertise in medicinal chemistry, molecular modeling, parasitology, DMPK and pharmacometrics, toxicology, formulation and scale-up chemistry.  Starting from the Early Lead, rational and systematic modifications will be made to further improve the overal properties based on state-of-the-art capabilities and data generated at MMV, GSK and University of Tokyo.  As the target of these molecules is an enzyme essential to the growth of the malaria parasite, and structural information is available, a structure-based drug design (SBDD) approach will be applied.

How can your partnership (project) address global health challenges?

Malaria caused approximately 627,000 deaths in 2020, mostly in children under five years of age and pregnant women. Malaria is caused by a parasite from the genus Plasmodium. In humans, five species of Plasmodium are known to cause the disease. Of particular relevance are P. falciparum, which is the most lethal and accounts for 93% of cases in sub-Saharan Africa and P. vivax which is prevalent in Southeast Asia and the Americas and causes post-treatment disease relapse due to a latent liver form of the parasite. Current antimalarial control is highly dependent on artemisinin combination therapies (ACTs) which require multiple doses, and it is concerning that decreased parasite sensitivity has emerged to all currently-used ACTs, leading to significant failure rates in parts of Southeast Asia where partner drug resistance is evident. If resistance becomes widespread in Africa (where most deaths occur), a major health crisis is feared. In response to this impending crisis and with the eventual aim of eradicating the disease, new drugs with novel modes of action which overcome known resistance associated with existing therapeutics are needed. Development of compounds which can also be used in chemo-protection/prevention, in addition to acute treatment, will be valuable to help drive eradication. This project, due to the novel mode of action will add to the therapeutic options available to drive the malaria elimination goal.

What sort of innovation are you bringing in your project?

The series is chemically novel, has a novel mode of action and a unique parasitological profile and could be applied to treatment of uncomplicated malaria with the added benefit of killing liver stages. The team will be using modern drug discovery approaches including structure-based drug design and protein crystallography (supported at MMV partners), to ultimately identify a preclinical candidate from this project. This multidisciplinary team has the necessary expertise and capabilities to deliver a novel option for treatment or prophylaxis. 

Role and Responsibility of Each Partner

The GSK, University of Tokyo and MMV collaborators will be fully integrated in the running of the project, including design, synthesis and biochemical and parasitological profiling of new compounds to achieve the project objectives. GSK and MMV will apply their expertise in medicinal chemistry, including structure based techniques, to optimise compounds. GSK will apply their expertise in ProRS biochemistry to characterise compounds and University of Tokyo will perform key parasitology studies on compounds to assess potency and resistance generation risks. Some activities will also be conducted at contract research organizations and via partners in the MMV network. The overall scientific leadership will be jointly held by representatiaves from all Collaboration Partner organizations.