Predicting and controlling higher order structures for the development of therapeutic peptides


   Strathclyde Institute of Pharmacy & Biomedical Sciences

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  Dr Z Rattray  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Background

Peptide drug candidates (PDCs) and their lipidated forms represent a growth area in delivering new therapeutic modalities for addressing unmet clinical need. Unmodified PDCs generally suffer from low circulation half-lives, requiring multiple dosing, chemical modifications to prolong circulation half-life, or incorporation into controlled release delivery systems. Lipidated PDCs have emerged as a promising strategy to prolong systemic exposure to PDCs. However, their propensity to self-associate under formulation conditions has hampered their clinical translation. An underpinning gap in our knowledge base regarding PDC development is understanding the molecular determinants which define PDC self-association.

Project Objective

Undesirable developability attributes pose a major drawback to the clinical and commercial translation of chemically-modified (e.g., lipidated) PDCs. The commercial translation of these drug products is often hampered by a lack of fundamental knowledge of their solution-phase behaviour and the interactions that drive self-association. The term aggregation encompasses many types of interactions promoting self-association, ranging from dimerization to fibrillation. Aggregates can pose severe developability risks, including reduced therapeutic efficacy, immunogenicity, and adverse events. A key challenge and research question in the development of biotherapeutics is defining the sequence and structural determinants that influence undesirable developability attributes. Through developing a computational and analytical framework a number of critical research questions concerning lipidated PDC developability will be addressed:

The objective of this studentship is to develop an integrated computational and analytical framework for understanding the mechanisms driving PDC aggregation. This information will then be used to guide chemical and formulation-based strategies to mitigate self-association. The desired outcome will be a framework to design next-generation PDCs with enhanced physicochemical properties for downstream therapeutic development.

Academic Environment 

This project is a joint interdisciplinary collaboration between the Rattray and Burley laboratories situated within the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS) and Pure and Applied Chemistry (PAC), and industrial supervision from Dr Robin Capomaccio and Dr Kevin Treacher (AstraZeneca). This project is ideally suited to highly-motivated and talented students with a keen interest to work at the interface of drug delivery and analytical disciplines. Candidates are expected to possess at least an upper second-class degree (or equivalent) in a relevant Pharmacy, Pharmaceutical Sciences, Biosciences, Biochemistry, Chemistry, or Engineering backgrounds. The successful candidate will receive training on a wide range of highly desirable technical skills including and not limited to chemical biology, solid phase synthesis of peptides, analytical flow field flow fractionation modalities, particle analysis techniques in Strathclyde state of the art facilities. 

The successful candidate will also benefit from a Postgraduate Certificate in Academic Practice from the University of Strathclyde. The student will benefit from working and interacting with the staff and students in two highly-vibrant and multidisciplinary teams across PAC and SIPBS. The University of Strathclyde is currently ranked second for Pharmacy and Pharmacology in the UK Complete University Guide.


Biological Sciences (4) Chemistry (6) Engineering (12) Medicine (26)

Funding Notes

This is an EPSRC Industrial CASE studentship in collaboration with AstraZeneca Pharmaceuticals (AZ). The successful applicant will be expected to spend at least 3 months working in the Macclesfield New Modalities Product Development site. This studentship is open to UK students and includes a stipend and fees for 4 years. Candidates must have a strong background in Physical Chemistry, Biological Chemistry, or Biochemistry and have obtained a (i) or 2(i) degree. Candidates who are interested in this position are encouraged to send their CV and contact details of two referees to [Email Address Removed].

References

1- Biskupek I, et al (2022). Biomolecules. 12(8):1140. doi: 10.3390/biom12081140.
2- Tartaglia GG, et al (2005). Protein Sci. Oct;14(10):2723-34. doi: 10.1110/ps.051471205.
3 - Zapadka, KL, et al (2016). Journal of the American Chemical Society 138(50): 16259-16265. 4- Frederiksen, TM, et al (2015). Biophysical journal 109(6): 1202-1213.
5- Marassi, Valentina, et al (2022). " Molecules 27(17): 5485.