Peptide Discovery

We have designed Y2 selective and long-acting PYY analogues by the screening of large collections of analogues (arrays) as well as more in-depth SAR analysis. We were able to identify analogues with much improved Y2 selectivity and stability against C-terminal degradation and in combination with fatty acid derivatization we show that improved PK can be obtained that otherwise is not achieved using lipidation only.

PL8177 OCD (oral, colon delivery) is a Eudragit® functional polymer formulation designed to release the selective MC1r agonist PL8177 throughout the entire GI tract. The gut lining is rich in cell surface MC1r receptors expressed on the epithelium, allowing direct target engagement by PL8177. The lack of membrane permeability of PL8177 results in zero absorption, avoiding any potential systemic effects.

Ciraparantag is under investigation for use as an anticoagulant reversal agent. It physically associates with Novel Oral Anticoagulants (NOACs) and heparins allowing rapid re-establishment of a normal blood coagulation state. Ciraparantag is a small novel synthetic water soluble peptide which poses unique challenges since it could also be characterized as a small molecule. The complexities associated with the synthesis and purification will be presented.

PRI-002 prooved to eliminate already formed, toxic Aβ oligomers and to reverse cognitive deficits even in old-aged transgenic Alzheimer’s disease (AD) mice with full blown pathology and deficits, even by oral administration. Oral treatment also improved cognition in cognitively impaired old Beagle dogs as a non-transgenic AD model. PRI-002 is blood-brain-barrier penetrable and demonstrated successful target engagement also in vivo and ex vivo. I will summarize successful in vivo proof-of-concept in five treatment studies in four different animal models in four different laboratories. I will also report the SAD and MAD phase I clinical data for PRI-002.

The presentation will explore how peptides can be extracted from nature, used as assurance of food safety and can be exploited for the promotion of health. The application of cutting-edge technologies such as mass spectrometry and peptidomics has revolutionised these fields and accelerated the development of novel, healthy and sustainable foods.

The Australian Research Council (ARC) has recently announced they would provide $35 million to establish a research centre investigating peptides and proteins. The ARC Centre of Excellence for Innovations in Peptide and Protein Science (CIPPS) will be headquartered at The University of Queensland and led by Professor David Craik. There are 13 other Chief Investigators across six Australian universities, eight Partner Investigators and 21 Partner Organisations over the world. CIPPS strives to build a critical understanding of peptides and proteins in order to unleash the potential of these biomolecules for human benefit. The three key research themes of the Centre are to discover nature’s untapped reservoir of peptides and proteins, decode their structures and functions, and develop enhanced synthetic technologies to address biology’s next grand challenge – the design of peptides and proteins for targeted scientific, agricultural, biotechnology, animal health and pharmaceutical applications.

Plant defensins with potent antifungal activity have the potential to be developed as effective and robust treatments for fungal infections in humans. Hexima’s lead drug candidate, HXP124, has potent antifungal activity and efficiently penetrates human nails. HXP124 is being developed as a fast, effective topical treatment for fungal nail infections (onychomycosis).

High-density outbreaks of crown-of-thorns starfish (COTS, Acanthaster planci) are frequent and responsible for dramatic loss of live coral. Current control approaches are ineffective because they involve divers culling individual COTS. We have discovered that COTS communicate by using secreted proteins as attraction and warning signals. The goal is to develop these proteins into peptide-based baits as a scalable bio-control solution to the COTS threat.

Bringing a novel pesticide to market is typically the work of multi-national companies. Combine this with a naturally expressed group of peptides as the bio-active compounds, which no regulator has ever examined and it’s either a romantic comedy or a horror story - with lessons for those committed to safe and sustainable food and fibre production around the world. This is the story a small R&D company based in regional Australia who climbed every regulatory mountain to bring a new active constituent and product to market: how did they get there and what are the lessons for researchers, innovators and regulators?

Polyphor has been one of the leading companies to start drug discovery using its macrocyclic peptide technology starting from early 2000s. While licensing its programs in later stages of development was a common strategic choice, Polyphor has decided to run two Phase III programs in critical healthcare areas – oncology and antibiotiotics. Today, one of these programs was unsuccessful while the second program in oncology successfully continues. With this talk, we aim to provide you the challenges and advantages of having a broad spectrum from drug discovery to late stage development as a peptide focused biotech. What are the learnings we were able to apply to early stage development from our late stage failures? How do we optimize our strategic choices? How did Polyphor come up with the best in class molecule targeting a well-recognized but a tough target that many others have failed? What are the considerations we have in preparing for a launch of a macrocyclic peptide oncology drug?

Solid-Phase Peptide Synthesis (SPPS) is the method of choice for the synthesis of peptides in both industrial and research modes. In terms of the circular economy, several of the steps involved in an SPPS process should be greener. In this presentation, we will summarize the recent efforts of our group to make SPPS a Green Process.

Peptides from nature are innovative lead compounds for the development of G protein-coupled receptors ligands, since they cover a chemical space, which differs from that of synthetic small molecules. We utilize plants and invertebrates to discover, isolate, chemically synthesize and map their signaling profile and pharmacology on human receptors

We have applied genome-wide chemogenomics in mammalian cells using CRISPR/Cas to deconvolute the target of the natural product Cavinafungin. Cavinafungin scored as a potent and selective hit targeting viruses of the flavivirus family. Our data identified that it targets the signal-binding cleft of the host endoplasmic reticulum signal peptidase.

The pharmacokinetics of a therapeutic peptide is critical in the translation from research to the clinic. The very nature of peptides like susceptibility to proteolytic degradation pose challenges in early development. A nonclinical case study will be presented to demonstrate the package of information to de-risk the development of a peptide therapeutic. A number of animal models were used to demonstrate adequate exposure in the relevant, pharmacodynamic compartment. Lessons learned from this development program will be shared in the context of clinical development.

Peptide mapping is an important and critical technique in the characterization of biopharmaceuticals. These separations are based upon reversed-phase liquid chromatography that can be coupled to mass spectrometry (RP LC-MS). The need currently exists for robust and reproducible methods to allow for deployment of sensitive assays. Recent observations have shown that column hardware should also be given serious consideration to improve assay reproducibility and sensitivity. Specifically, metal-ion mediated adsorption in liquid chromatography (LC), which is due to electron-deficient surfaces such as metals, has been observed as a contributing factor to poor peak shape, tailing, and diminished recovery of sensitive analytes. To combat this, a specialized, inert LC surface can be used towards the column hardware. Substantial gains in chromatographic performance, MS sensitivity, and recovery along with higher quality peptide mass spectra can be achieved. The value of novel inert surfaces to improve recovery, assay reproducibility, and MS quality is critical for peptide mapping of protein therapeutics using MS-friendly formic acid-based peptide separations.

PRI-002 proved to eliminate already formed, toxic Aβ oligomers and to reverse cognitive deficits even in old-aged transgenic Alzheimer’s disease (AD) mice with full blown pathology and deficits, even by oral administration. Oral treatment also improved cognition in cognitively impaired old Beagle dogs as a non-transgenic AD model. PRI-002 is blood-brain-barrier penetrable and demonstrated successful target engagement also in vivo and ex vivo. I will summarize successful in vivo proof-of-concept in five treatment studies in four different animal models in four different laboratories. I will also report the SAD and MAD phase I clinical data for PRI-002.

Chemical stability is deemed as a critical aspect for peptide drug design, selection of administration route, and the assessment of manufacturability for both drug substance and drug product. Even though accurate prediction of peptide stability remains a demanding challenge, there is a plethora of peptide stability/degradation studies from where patterns of peptide degradation might be tentatively generalized based on the key structural moieties. The subject talk will center on ubiquitous peptide degradation such as hydrolysis, rearrangement, elimination/fragmentation, addition, etc., and their correlation to peptide sequence/chemical structure, which could be instructive for peptide drug design and stability investigation. In addition, general side reactions during peptide chemical synthesis will be introduced. These two topics are intrinsically interrelated.