Permeability-limited bifunctional antimalarials

Project

Project Title: ‘Permeability-limited bifunctional antimalarials’

Studentship: UK Research and Innovation (UKRI), Expanding European in Excellence in England (E3)

Research themes: Malaria and other vector borne diseases

Primary Supervisor: Professor Jeremy Burrows

Abstract

Malaria, an infection involving the apicomplexan parasite Plasmodium, remains one of the leading infectious diseases with an estimated 610,000 deaths in 2024. Symptoms develop as a result of the body’s reaction to high parasitemia resulting from proliferation of asexual stages in human erythrocytes. The Plasmodium infected erythrocyte has significant nutritional demands such that the cell is remodelled to include new permeability pathways (NPPs) facilitating access by larger molecules to the parasite. Data show that compounds having low passive transcellular permeability nevertheless are able to kill Plasmodium including from mechanisms that require, for example, parasite cytosol or digestive vacuole localisation, suggesting that low permeability compounds can, nevertheless, access core parasite machinery even if protected through multiple membranes.

We, thus, hypothesise that low permeability inhibitors of parasite growth constitute an unique strategy and opportunity to selectively target the parasite over the host. One issue, however, of having low permeability is the low likelihood of high systemic absorption via the oral route – traditionally the main administration for treatments of uncomplicated malaria or chemoprevention. However, when considering parenteral administration either i.v., i.m. or s.c. which are established priorities for severe or complicated malaria or long acting chemoprevention, then permeability constraints are overcome.

The objectives of this project are to:

1. Establish pragmatic physical property and molecular size constraints on parasite access with low permeable small molecules.
2. Confirm the role of NPPs in parasite access by low permeability compounds; this will be explored by using known inhibitors of NPPs in the presence of physiologically relevant media.
3. Design bifunctional small molecules (typical molecular weights >800) that involve connecting known potent inhibitors, in a “structure activity relationship tolerant” fashion, so as to ensure delivery of the correct physical properties for the target product profile and the retention of equal functional potency on each of the relevant orthogonal targets.

Target pairs will be selected to maximise impact on the lifecycle and complement the global antimalarial portfolio. Such bifunctional molecules will be profiled for cross resistance and de novo resistance selection; the expectation is that such a “combination-in-one-molecule” could be a rational strategy to reduce resistance risk. In addition, the low host-cell permeability, combined with parasite-induced permeability pathways, may be exploited to explore the cellular toxicology benefits of such approaches including cytotoxicity and teratogenicity. Bispecific compounds will thus be synthesised and profiled with attractive frontrunners meeting advanced drug discovery in vitro criteria, being tested in vivo to determine the compound concentration time course both for i.v. and potentially i.m. depending on the target product profile potential.

Translational Aspects

This project is focused on malaria, an infectious disease of global priority. We seek an improved mechanistic understanding of non-oral permeability limited compounds’ access to the parasite and the implications this could have on host selectivity. This in turn can enable principles for therapeutic intervention with hypotheses tested early in preclinical studies. In particular it could open up areas for therapeutic antimalarial discovery previously seen as liabilities.

The studies with NPP inhibitors will not only provide greater understanding of compound access to the parasite but will also frame NPPs as a suitable biological target in its own right. Defining the criteria for parasite access will inform future antimalarial drug discovery.

Project outcome will communicate potential of bifunctional platform for academic, industrial and PDP (e.g. Medicines for Malaria Venture) malaria discovery.

Methodological Aspects

This project combines synthetic organic and medicinal chemistry, biophysics, pharmacology, parasitology, and pharmacokinetics to understand and predict physical property constraints on Plasmodium asexual blood stage potency and potential for different target product profiles. It includes the following:

• Synthetic organic and medicinal chemistry: Selection and synthesis, purification and characterisation of low-permeability mono- and bi-specific organic small molecules.
• In vitro parasitology models: Use of defined culture systems with sensitive and drug-resistant Plasmodium strains to test functional potency in the presence/absence of NPP inhibitors.
• In vitro pharmacology: Selection of low permeability bifunctional compounds for cytotoxicity and teratogenicity (human iPSC) testing and interpretation of data.
• Biophysics: Selection for testing of molecules spanning the range of required physical property parameters. Analysis of data to inform parasite-accessibility requirements.
• Pharmacokinetic studies: On frontrunners to work with PK experts to interpret the in vitro metabolism and in vivo profiles of parenteral administration of compounds.

Expected Outputs

The expected outputs of this project include both scientific deliverables and translational impact.

Scientific outputs:

• Comprehensive datasets regarding permeability, NPP involvement and asexual blood stage potency leading to molecular property understanding required for parasite access.
• Prioritisation and synthesis of mono- and bi-functional inhibitors.
• Data regarding parasitology and cytotoxicity including functional potency contribution of each biological target.
• Pharmacokinetic profiling of most advanced compound(s).
• At least two first-author publications in peer-reviewed journals in the fields of medicinal chemistry, parasitology, or infectious diseases.
• Presentations (oral/poster) at national and international conferences on antimalarial drug discovery or medicinal chemistry.

Anticipated Impact:

• An increased understanding of the opportunities from low-permeability parenteral antimalarials in particular related to selective parasite vs host access.
• Development of predictions of asexual blood stage accessibility based on physical properties.
• Open up “larger” small molecule chemical space for parenteral antimalarial drug discovery – relevant in the context of long acting injections and severe malaria.

Development Opportunities

a) Advanced Quantitative/Data Science Skills

During Year 1 of the programme you will be required to attend and participate in mandatory core competency training modules attached to the MSc Health Data Science programme delivered at the Lancaster University campus. These modules normally run in-person between October and December. During this time, you may be expected to attend on-site at the LU campus between 2-5 days each week. A timetable for these modules will be confirmed prior to enrolment.

You will also be required to attend one further optional module, delivered at the LU campus, which normally run between 2-4 week blocks in-person between January and April.

Training in advanced quantitative and data‑science skills will equip the student to analyse complex biological, chemical and pharmacokinetic datasets central to this project. These skills will support modelling of permeability, interpreting parasite‑growth and NPP‑inhibition data, and integrating multi‑parameter profiles to guide compound design. Access to Lancaster’s Health Data Science modules will strengthen the student’s ability to handle large, multidimensional datasets and extract mechanistic insight—an increasingly essential capability in modern drug discovery.

You will not be required to undertake assessments attached to the LU MSc Health Data Science programme.

b) Project-Specific Skills

The student will receive training in organic synthesis, purification and characterisation. They will also be trained on antimalarial medicinal chemistry, priority biological targets and associated inhibitors with SAR and design strategies for bifunctional compounds. The student will receive training on target product profiles and the malaria drug discovery landscape, and thus, how this work could inform future strategies.

Training will be provided to run in vitro growth inhibition assays of Plasmodium falciparum in the presence and absence of NPP inhibitors and how to interpret physical property and in vitro and in vivo pharmacokinetic experiments. The student will benefit from interdisciplinary supervision and collaboration with experts in parasitology, medicinal chemistry, pharmacology and pharmacokinetics. They will participate in lab meetings and work closely with chemists at the Department of Chemistry at the University of Liverpool. Finally, they will have access and training in drug design for global health (dd4gh) – the MMV medicinal chemistry AI/Machine-learning design tool.

Relevant Publications

• DOI: 10.1016/0166-6851(83)90008-7
• DOI: 10.1016/j.cell.2011.05.002
• DOI: 10.1038/nrmicro2110
• DOI: 10.1017/S0031182013000826
• DOI: 10.1186/s12936-024-05128-1

What we are looking for

A background in chemistry, particularly synthetic organic chemistry, is required. Knowledge and practical expertise in parasitology, pharmacology, biochemistry, or a related discipline is desirable. A strong interest in organic synthesis for biological and physicochemical profiling is required.

The student should demonstrate analytical and problem-solving abilities, attention to detail, proficiency in literature searching and data analysis, as well as enthusiasm for experimental work predominantly in a chemistry lab, but also in parasitological testing, where training will be provided. Good communication and teamwork skills, along with motivation to learn interdisciplinary methods and engage in translational research, will be essential for success in this project.

Indicative Start Date: 1st October 2026

Funding Package

This studentship is funded by the UK Research Innovation (UKRI), Expanding European Excellence (E3).

The studentship includes:

• Stipend set at the UKRI Minimum Doctoral Stipend rate. For 26/27 this is £21,805 per annum.
• Tuition/programme fees
• Contribution to research support fees for: lab consumables, travel, computing hardware, publications.

The duration of the funding package is 4 years.

Eligibility

Academic

• Applicants must hold at least a first class or high upper second-class Honours degree, or a degree of comparable standard awarded from outside the UK.
• A Masters degree (at merit or distinction preferable) is also a pre-requisite.
• Where an applicant does not meet the Honours degree requirement (e.g. they hold a lower second-class Honours degree), they may be eligible to apply if they also hold a Master’s degree with an awarded distinction in an area relevant to the research theme of the project. To be considered for this exemption, the qualification must be awarded at time of application and candidates must provide an award certificate and transcript for both qualifications. Unfortunately, we are unable to consider Master’s qualifications that have not yet been awarded for this purpose.

Residence

THIS OPPORTUNITY IS ONLY AVAILABLE TO CANDIDATES HOLDING A ‘HOME’ FEE STATUS.

‘Home’ fee status typically applies to students who are ‘settled’ in the UK—meaning they have no immigration restriction on the length of stay—and who have been ordinarily resident in the UK, the Republic of Ireland, the Channel Islands, or the Isle of Man for the three years immediately before the first day of their course. Eligibility also extends to certain groups such as British or Irish nationals, those with Indefinite Leave to Remain or equivalent rights, refugees or individuals with humanitarian protection, and some family members of qualifying persons.

IF YOU ARE UNABLE TO PROVIDE EVIDENCE THAT YOU HOLD A ‘HOME’ FEE STATUS, YOUR APPLICATION WILL BE REJECTED.

How to Apply

Stage 1 – Complete the following online form

Candidates are eligible to apply from Monday 18th May 2026.

In order to be considered for this opportunity, candidates must:

1. Submit a copy of their Curriculum Vitae to pgr@lstmed.ac.uk
2. Complete the following form: https://forms.office.com/e/PRhUAg6dG0

This application form will ask you to:

• Provide your personal details
• Answer 6 questions related to your motivation for doctoral study (up to 1250 characters [approx 250 words] per question)
• Detail your qualifications, any relevant research experience and your English language proficiency
• List any contextual information that you feel is important for assessors to know (optional)
• Provide diversity monitoring information

Deadline for application is noon UK time Monday 8th June. Applications are only considered complete if LSTM has received a copy of your Curriculum Vitae and a completed form.

Successful Candidates

Candidates that are successful will be notified by Friday 26th June.

Successful candidates will be invited to submit documentation in support of the information they provided in their initial application prior to interviews expected to take place early July.