The University of Bristol is offering a fully funded PhD project focused on developing targeted covalent macrocycles (TCMs) as pathway-specific inhibitors of the complement system, with potential applications in inflammatory and autoimmune diseases.
The project will combine phage display, peptide chemistry, molecular biology, biophysical analysis, structural biology, proteomics, and bioinformatics to develop selective inhibitors targeting the complement proteins C1s and factor D.
About the Research Project
The complement system plays an important role in immune defense and tissue homeostasis. However, excessive or dysregulated complement activation can contribute to inflammatory and autoimmune diseases.
This PhD project aims to develop more selective complement inhibitors by targeting enzymes involved in specific complement activation pathways rather than broadly suppressing the complement system.
The research will focus on:
- C1s, a serine protease involved in the classical complement pathway.
- Factor D, a rate-limiting serine protease involved in the alternative complement pathway.
The project will investigate whether targeted covalent macrocycles can selectively inhibit these proteins and potentially provide new therapeutic approaches for diseases such as heparin‑induced thrombocytopenia and atypical haemolytic uremic syndrome.
Key Research Objectives
1. Targeting C1s and Factor D Using Covalent Phage Display
The project will use a phage display screening platform to identify targeted covalent macrocycle inhibitors against C1s and factor D.
The researcher will work with large phage-displayed peptide libraries and use chemical linchpins containing electrophilic warheads to generate macrocyclic peptides for screening.
Next‑generation sequencing will then be used to identify enriched candidates following multiple rounds of selection.
2. Characterisation of TCM Inhibitors
Selected macrocycles will be synthesized and evaluated for potency and selectivity using:
- Protease activity assays
- Biophysical techniques
- Complement‑specific assays
- Chemical proteomics
- ELISA‑based complement activation assays
- Sheep blood haemolytic assays
3. Structural Basis of TCM‑Mediated Inhibition
Structural studies will be used to understand how the selected macrocycles interact with C1s and factor D.
The resulting structures will support structure‑guided optimisation of properties such as selectivity and proteolytic stability.
Potential Research Directions
This is an interdisciplinary PhD project with opportunities for the student to develop expertise in areas such as:
- Phage display technology
- Chemical library development
- Targeted covalent macrocycles
- Structural biology
- X‑ray crystallography and cryo‑EM
- Bioinformatics and analysis of phage display sequencing data
- Complement activity assays
- Microbiology and bacterial infection models
Students may also explore the impact of selective complement inhibition on the killing of encapsulated bacterial pathogens using human serum.
Skills Required
The project combines several scientific disciplines, including:
- Phage display
- Molecular biology
- Microbiology
- Immunology
- Protein biochemistry
- Peptide chemistry
- Structural biology
- Bioinformatics
- Next‑generation sequencing
- Proteomics
- Complement biology
- Drug discovery
Project Supervisors
Dr Maisem Laabei
Dr Scott Lovell
For more phage‑related PhD opportunities, check here
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PhD in Phage Display & Immunology At University of Bristol employer: The Phage
The University of Salford offers an exceptional opportunity for aspiring researchers in the field of bacteriophage therapy, providing a collaborative environment with leading institutions like the University of Liverpool and the University of Limerick. With a strong focus on advancing oral health through innovative research, the university fosters a supportive work culture that encourages professional growth and development, while also contributing to meaningful solutions for global health challenges. This PhD position not only allows for hands-on laboratory experience but also promotes collaboration across disciplines, making it an ideal setting for those passionate about tackling antimicrobial resistance.
