Expanding the biological diversity of chemical probes to ligand the ‘dark’ proteome

Identifying and exploring new biologically-relevant chemical space is a major challenge, central to both chemical biology and medicinal chemistry. Access to high quality chemical probes dramatically influences the scope of experimentally-investigated biomedical science and is crucial for validating novel targets. Small molecule drugs continue to dominate our collective ability to treat disease, yet identifying new biologically-relevant chemical space is hampered by the dominance<br /> of a narrow reaction toolkit. With the advent of reactive fragments, and the powerful companion technology of chemical proteomics, we now envision the prospect of mapping biological coverage systematically in a native cellular context.<br /> <br /> In this project, we will develop connective reactions that enable the one-pot, plate-based synthesis of diverse sets of distinctive reactive fragments (RFs). The synthetic approach will contrast starkly with the typical multi-step synthesis of fully-functionalised probes; as well as the simple amide coupling chemistry that generally drives direct-to-biology experimentation. To broaden explorable chemical space, prioritised chemistries lie outside the reaction toolkit that currently dominates discovery. Furthermore, to complement existing cysteine-directed RF sets, we will deliberately exploit electrophilic &ldquo;warheads&rdquo; with distinctive (particularly lysine-directed) reactivity. Having established this capability, we will: (a) investigate extension of direct-to-biology experimentation beyond amide coupling chemistry; and (b) execute biological mapping of the distinctive RFs using chemical proteomics and machine learning. We will thus demonstrate that diverse RF sets, accessible via the new chemistries, can enable liganding of the &ldquo;dark&rdquo; proteome.<br /> <br /> This project is collaborative with GSK.

<p>The studentship will be collaborative with the chemical biology group at GSK and within <a href="https://astbury.leeds.ac.uk/">The Astbury Centre</a> at the University of Leeds.</p> <p>One-pot, plated-based methods will be developed to enable the preparation of chemically and biologically diverse reactive fragment (RF) libraries. The RFs will bear electrophiles that complement existing libraries accessible within GSK and may optionally contain clickable alkyne tags to enable a full suite of chemical proteomic workflows.</p> <p>The specific scientific objectives are:<br /> 1. To develop connective plate-based chemistries to access diverse distinctive RF sets.&nbsp; The student will develop and apply novel connectvie chemistries in the synthesis of diverse sets of RFs.&nbsp;&nbsp;The student will thereby determine the scope and limitations<br /> of the connective chemistries for preparing diverse RF sets (to feed into Objs 2 &amp; 3).</p> <p><br /> 2. To explore the suitability of the new connective plate-based chemistry for high-throughput direct-to-biology experimentation.&nbsp;&nbsp;The student will explore the potential of the new connective chemistries to extend direct-to-biology experimentation beyond simple amide coupling.&nbsp; Here, new ligands for a specific protein will be idnetified using protein mass spectrometry.&nbsp; The student will thereby determine whether new connective chemistries can expand the chemical space explorable in direct-to-biology workflows.</p> <p><br /> 3. To harness chemoproteomics to evaluate the proteome-wide reactivity of RF libraries and deploy machine learning tools to direct further library design towards the &lsquo;dark&rsquo; proteome.&nbsp;&nbsp;The student will assess the reactivity and selectivity of the tagged RFs (from Obj. 1) in complex biological environments.&nbsp; Here, Leed&rsquo;s new chemical proteomics platform will be exploited in conjunction with new machine learning tools for data analysis.&nbsp;&nbsp;The student will thereby demonstrate the utility of the RF sets for proteome-wide labelling in lysates and live cells, and will also gain novel insights into target ligandability and selectivity in a cellular context.</p>

<p>Formal applications for research degree study should be made online through the&nbsp;<a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University&#39;s website</a>. Please state clearly in the Planned Course of Study section that you are applying for <em><strong>PHD Chemistry</strong></em> and in the research information section&nbsp;that the research degree you wish to be considered for is <em><strong>Expanding the biological diversity of chemical probes to ligand the &lsquo;dark&rsquo; proteome</strong></em>&nbsp;as well as&nbsp;<a href="https://eps.leeds.ac.uk/chemistry/staff/4180/professor-adam-nelson">Professor Adam Nelson</a> as your proposed lead supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <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> <p class="MsoNoSpacing">Applications will be considered on an ongoing basis. &nbsp;Potential applicants are strongly encouraged to contact the supervisors for an informal discussion before making a formal application. &nbsp;We also advise that you apply at the earliest opportunity as the application and selection process may close early, should we receive a sufficient number of applications or that a suitable candidate is appointed.</p> <p>Please note that you must provide the following documents at the point you submit your application:</p> <ul> <li>Full Transcripts of all degree study or if in final year of study, full transcripts to date</li> <li>Personal Statement outlining your interest in the project</li> <li>CV</li> <li>Funding information including any alternative sources of funding that you are applying for or if you are able to pay your own fees and maintenance</li> </ul>

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. For this project, a Masters' Degree is also required in an appropriate discipline. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.0 overall with at least 5.5 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. Some schools and faculties have a higher requirement.

<p class="MsoNoSpacing">A highly competitive EPSRC Industrial Case Award in partnership with GlaxoSmithKline, consisting of the award of academic fees at the UK fee rate with a maintenance grant (currently &pound;17,668 in academic session 2022/23) for 4 years with an additional Top-Up of &pound;3,000 per year.<br /> <br /> This opportunity is open to UK applicants only. All candidates will be placed into the EPSRC Industrial Case Award Competition and selection is based on academic merit.<br /> <br /> Please refer to the&nbsp;<a href="https://www.ukcisa.org.uk/">UKCISA</a>&nbsp;website for&nbsp;information regarding Fee Status for Non-UK Nationals.</p>

<p>For further information about this project, please contact Professor Adam Nelson: e:&nbsp;<a href="mailto:a.s.nelson@leeds.ac.uk">a.s.nelson@leeds.ac.uk</a></p> <p>For further information about your application, please contact Doctoral College Admissions: e:&nbsp;<a href="mailto:maps.pgr.admissions@leeds.ac.uk">maps.pgr.admissions@leeds.ac.uk</a></p>