Covalent inhibition as an antimalarial strategy

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Project

Project Title: ‘Covalent inhibition as an antimalarial strategy’

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 majority of antimalarial hits, leads and candidate drugs from recent discovery efforts have been identified from phenotypic screening and, where targets have been identified, reversible inhibition of the Plasmodium biological target has either been confirmed or inferred. However, there has been very little focused attention on covalently inhibiting parasite targets beyond the non-specific covalency associated with compounds having reactive chemistry, such as the endoperoxides.

The goal of this DTP is to apply rational covalent design to inhibit 1-2 antimalarial biological targets where the target is known, is well characterised, has expressed protein for biochemistry and structural biology and, critically, meets the criteria for covalency. These criteria include having an invariant essential amino-acid nucleophile across Plasmodium spp. but not mammalian enzymes as well as there being available reversible ligands with geometries and vectors that support hypotheses for electrophilic functionalisation. We propose to select 1-2 Plasmodium biological targets meeting these criteria and where X-ray crystallography has confirmed the ligand binding site. Using the known reversible ligands, new inhibitors will be designed having appropriate electrophilic substituents such that the distance and vector for covalent bond formation with the protein is achievable.

The objectives of this project are to apply the state of the art regarding covalency to inhibition of Plasmodium spp. targets. This will be done through:

  1. Establishing clear covalency criteria for Plasmodium spp. target selection.
  2. Prioritising 1-2 targets meeting these criteria.
  3. Using docking and co-folding technologies to design, synthesise, purify and characterise compounds that have the potential to reversibly bind to a target and then position electrophilic warheads in proximity to amino acid nucleophiles for selective covalent bond formation.
  4. Confirming covalent binding through biochemistry, mass spec or structural biology.
  5. Confirming the impact of covalency on kill rate, resistance risk and pharmacokinetic-pharmacodynamic relationships.
  6. Exploring the potential for covalency to rescue essential targets that are considered undruggable due to their need for >99.9% inhibition; answering this question alone would open up huge areas for exploitation.

Given the potential pharmacokinetic liabilities of a covalent inhibitor and the fact of a 48h Plasmodium intra-erythrocytic lifecycle, in addition to the potential for oral delivery, parenteral administration will be considered in the design of frontrunner compounds. In principle, a long acting injection of a covalent inhibitor, provided tolerability and stability criteria are met, could deliver significant efficacy even with a relatively short predicted half-life in vivo.

Translational Aspects

This project is focused on malaria, an infectious disease of global priority. We seek an improved mechanistic understanding of the impact of covalency on antimalarial kill rate, resistance and functional potency in particular for high value, essential biological targets that have been considered undruggable due to the degree of inhibition required with a reversible inhibitor. Furthermore, we seek an understanding of the impact on PK-PD and dose prediction both for oral and parenteral administration. This could open up hitherto unfeasible biological targets for therapeutic intervention for antimalarial discovery.

Defining the criteria for Plasmodium spp. criteria will support the community in a similar way to the impact of Target Product Profile manuscripts.

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, medicinal and computational chemistry, biochemistry, biophysics, pharmacology, parasitology, and pharmacokinetics to understand, predict, define and explore the impact of covalency in antimalarial drug discovery. It includes the following:

  • Synthetic organic, medicinal and computational chemistry: Selection and synthesis, purification and characterisation of Plasmodium spp. target inhibitors having selected covalent warheads appropriate for the amino acid nucleophile. Design will involve co-folding or docking and viewing of potential inhibitors in 3D to prioritise for synthesis.
  • In vitro biochemistry and parasitology: In collaboration with biological groups globally and through hands on work at LSTM – testing of compounds on biochemical targets under different conditions – particularly time dependence, evidence through mass spec of covalent bond formation with a biological target, structural biological evidence of covalency and functional evidence of potency on the parasite through testing on established in vitro culture conditions, including rate of kill and resistance studies.
  • In vitro pharmacology: Cytotoxicity and teratogenicity (human iPSC) testing and interpretation of data.
  • Biophysics: Selection for testing of molecules and analysis of data.
  • Pharmacokinetic studies: On frontrunners to work with PK experts to interpret the in vitro metabolism and in vivo profiles of any compounds tested, along with potential based on in vitro PKPD studies.

Expected Outputs

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

Scientific outputs:

  • Criteria for selection of a biological target for antimalarial covalent inhibition.
  • Prioritisation and synthesis of electrophilic inhibitors with potential for covalent inhibition to a biological target.
  • Data regarding biochemistry, parasitology and cytotoxicity including time dependent potency, evidence of covalency, impact on functional potency, rate of killing and resistance studies.
  • 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 of covalent inhibition for antimalarial drug discovery.
  • Development of criteria for selection of a biological target and inhibitor series to maximise successful covalent inhibition.
  • Open up antimalarial drug discovery to high value, essential biological targets that have been down-prioritised by the community due to an inability to inhibit them easily >99.9%.

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 and computational tools to aid design. They will be trained in the factors influencing covalency and biological target prioritisation. The student will receive training on target product profiles and the malaria drug discovery landscape, and thus, how this work could inform future strategies.

Certain assays and data will be performed through global partnerships; however, training will be provided to run in vitro biochemical assays and in vitro growth inhibition assays of Plasmodium falciparum 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 biochemistry, parasitology, structural biology, computational chemistry, 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.

Relevant Publications

  • DOI: 10.1038/nrd3410
  • DOI: 10.1021/acs.jmedchem.8b01153
  • DOI: 10.1021/acsinfecdis.0c00684
  • DOI: 10.1371/journal.pone.0030949
  • DOI: 10.1126/scitranslmed.aaa6645
  • DOI: 10.1038/nsmb.3061

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/LYVnCuU4ar

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.

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