Award details

TargoPep: A cell-selective therapeutic delivery platform directed by non-toxic cell penetrating peptides

Reference	BB/X512242/1
Principal Investigator / Supervisor	Professor Glenn Burley
Co-Investigators / Co-Supervisors	Professor Simon Mackay, Professor Yvonne Perrie
Institution	University of Strathclyde
Department	Pure and Applied Chemistry
Funding type	Research
Value (£)	200,474
Status	Current
Type	Research Grant
Start date	01/03/2023
End date	31/05/2024
Duration	15 months

Abstract

The traditional drug discovery pipeline has traditionally developed small molecules to interact with protein targets. This has typically involved the design and synthesis of small molecules binding to hydrophobic clefts, which upon interaction with a small molecule, results in an alteration in protein function. However, a major limitation with this approach is that only 15% of the proteome is considered 'druggable' by small molecules. Modern drug discovery approaches are now expanding into the 'undruggable' space and interacting with other disease-relevant biomolecules, such as RNA, protein-protein, and protein-RNA interfaces. One major caveat in targeting this 'undruggable' space is molecules are larger in molecular weight and display sub-optimal physicochemical properties, such as poor cell uptake and distribution, as well as off-target accumulation in organs. Thus, a major unmet challenge is to establish a platform technology for the effective, cell-selective delivery of therapeutic payloads. TargoPep is a Strathclyde-based spin-out company dedicated to developing a new therapeutic platform for the cell-selective delivery of therapeutic payloads. The overall objective of this Follow-on-Fund proposal is to exemplify our first-generation, patented cell penetrating peptide (CPP) technology. Bio-isosteric replacement of key amino acid side chains will be explored and evaluated for their cell-selective uptake properties. This information will then be used to identify promising candidates their incorporation into liposomal formulations and to prepare discrete bioconjugates with therapeutic oligonucleotides. This exemplification and biological evaluation profiling will provide a robust foundation for the utilization of the TargoPep CPP technology.

Summary

Many potent therapeutics fail in the latter stages of clinical development due to their accumulation in undesirable organs. This is a major bottleneck in the drug discovery journey for a variety of therapeutics, many of which exhibit excellent clinical potential if they reach their biomolecular target. However, off-target accumulation produces significant issues such as dose-related toxicities and/or dose-limited efficacies. Drug delivery platforms have the potential to transcend these limitations and provide a parallel approach to ensure therapeutic payloads reach their desired biological target in the desired cell, tissue, or organ. A prominent approach to delivering therapeutic payloads to a desired cell/tissue type is the use of targeting groups which recognise a unique feature on the cell surface and enhance the uptake of the drug payload. Typically, uptake of a therapeutic candidate into a target cell type results in the encapsulation, and in many cases sequestration of the payload into vesicles called endosomes. If the drug is not released, this reduces or curtails its potency, and the accumulation is a potential source of dose-dependent toxicity. This is particularly problematic for the delivery of therapeutic payloads into the brain in which the blood-brain-barrier provides an additional and formidable blockade for targeting neurodegenerative disorders. Cell penetrating peptides (CPPs) are sequences of natural amino acids typically 12-30 monomeric units in length, which enhance the uptake of therapeutic payloads. Transcending the cell and tissue barriers of therapeutics with sub-optimal drug-like properties can be achieved by either directly attaching a CPP onto the payload or incorporating a CPP into a liposomal envelope which is used as a mini vesicle. Although CPPs have proven cell uptake properties, the current state-of-the-art in CPP development for drug delivery applications has suffered from toxicity which has limited their clinical applications. Our patented technology is based on the identification of synthetic analogues of amino acids, which when incorporated into a CPP, are non-toxic and more effective at enhancing cell uptake and escaping the endosome relative to existing CPPs which are exclusively prepared using natural amino acids. This work leverages earlier BBSRC-funded breakthroughs by expanding the successful first-generation designs. This purpose of this grant is to advance a new delivery platform for cell-selective targeting of therapeutic payloads. Our approach, which is unique to other previous drug delivery strategies, is to develop analogues of the major classes of natural amino acids that will modulate cellular uptake and distribution properties, targeting specific cell types to direct desired target engagement in tissues/organs associated with the clinical condition. These CPPs will be utilized in conjunction with a liposomal delivery vector developed to maximise the versatility of end-user application. The ambition is to enhance cell targeting and uptake features of these amino acids when incorporated into a CPP whilst reducing the toxicity issues related to existing CPP scaffolds.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Follow-On Fund (FOF) [2004-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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