LICAMM Discovering Connexin Inhibitors for Human Disease

How do cells communicate with one another? How do damage signals spread through tissues during disease and injury? And can we develop new medicines that interrupt these harmful processes while preserving healthy tissue?<br /> <br /> This interdisciplinary PhD project will address these fundamental questions by targeting Connexin 43 (Cx43), one of the most important cell-to-cell communication proteins in the human body. Cx43 forms channels that allow neighbouring cells to exchange chemical and electrical signals and plays essential roles in the normal function of the eye, heart, skin, and many other organs. However, increasing evidence suggests that Cx43 can also contribute to disease by facilitating the spread of damaging signals between cells, making it an attractive but largely unexplored therapeutic target.

<p>Despite extensive research highlighting the importance of Cx43, there are currently no selective small-molecule modulators that target this protein. Developing such molecules would provide powerful new tools for understanding Cx43 biology and establish the foundations for future therapeutic development across multiple disease areas.</p> <p>The primary aim of this project is to discover novel small-molecule inhibitors of Cx43 and understand how they influence its function. The student will use a multidisciplinary discovery pipeline that combines computational prediction, experimental validation, and molecular-level mechanistic studies to accelerate the identification of new Cx43-targeting compounds. Successful compounds identified during the PhD could form the basis of future optimisation and drug-development programmes aimed at delivering first-in-class Cx43-targeted medicines.</p> <p>The impact of this work could be substantial. In ophthalmology, Cx43 has emerged as a promising target for preserving corneal tissue, promoting wound healing, and potentially reducing the need for corneal transplantation. Additionally, Cx43 is the predominant connexin in the heart and is implicated in major cardiovascular conditions including arrhythmias, heart failure, myocardial infarction, and cardiomyopathy. Dysfunctional Cx43 signalling has also been linked to tissue injury, chronic inflammation, and impaired wound repair. Consequently, advances arising from this project could ultimately contribute to therapeutic strategies across a wide range of diseases affecting millions of people worldwide.</p> <p>The student will join a collaborative, multidisciplinary research environment and receive training in cutting-edge approaches used in modern biomedical research and drug discovery. This project is ideal for students with backgrounds in biological sciences, chemistry, pharmacology, biophysics, computational biology, biomedical sciences, physics, or related disciplines who are motivated by applying innovative science to major healthcare challenges.</p> <h5>References</h5> <ol> <li>Smith, K.A., E. Chuntharpursat-Bon, O. V Povstyan, M. Debant, J.A. Kinsella, C. Revill, C. Fagnen, J. Shi, R. Foster, D.J. Beech, and A.C. Kalli. 2025. Regulation of PIEZO1 channel force sensitivity by interblade handshaking. Sci. Adv. 11:eadt7046, doi: 10.1126/sciadv.adt7046.</li> <li>De Vecchis, D., D.J. Beech, and A.C. Kalli. 2021. Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension. Biophys. J. 120:1510–1521, doi: 10.1016/j.bpj.2021.02.006.</li> <li>Caseley, E. A.; Simmons, K. J.; Cole, B. A.; Flynn, A. J.; Muench, S. P.; Lippiat, J. D.  Large-Scale Structure-Based Virtual Screening Identifies Diverse KNa1.1 (KCNT1) Potassium Channel Inhibitors. Eur J Med Chem 313:118906 Article number 118906 Apr 2026. </li> <li>Wilkinson CG, Viswambharan H, Haywood NJ, Bridge KI, Turvey SJ, Armstrong T, Lunn L, Meakin PJ, Porter KE, Clavane E, Beech DJ, Cubbon RM, Wheatcroft SB, McPhillie MJ, Fishwick CWG, Kearney MT, Simmons KJ*. Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells. Molecular and Cellular Endocrinology (2024)112387. <br />  </li> </ol>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree.

If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements. The minimum English language entry requirement for postgraduate research study in the School of Medicine for 2027/28 is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

<p>This project is open to applicants who have the funding to support their own studies or who have a sponsor who will cover these costs.</p>

<p>For further information about the admissions process please contact the Faculty Admissions Team:<br /> e:<a href="mailto:hlspgradmissions@leeds.ac.uk">hlspgradmissions@leeds.ac.uk</a></p>