IN THE second of a series of articles for BTN, Phylogica's chief scientist, Dr Paul Watt, looks at why peptide therapeutics are attracting attention worldwide. Peptide therapeutics are drugs that target protein interactions in the treatment of disease. Peptides operate in the same space as the billion-dollar monoclonal antibody drugs, and it is believed by many that peptides will provide the next generation of blockbuster biological drugs.
One of the drugs in the new wave of natural peptide therapeutics to hit the market is Fuzeon (developed by Trimeris and licensed to Roche). It is a "fusion inhibitor" and it comprises a 36-amino acid peptide sequence derived from the gp41 protein the HIV-virus that prevents the entry of virus into CD4 cells. Fuzeon is an injectable therapeutic for AIDS and is the largest peptide for which large-scale chemical synthesis has been achieved. Annual Fuzeon sales revenue is expected to exceed $US200 million, based on current sales figures. Antibody replacement therapeutics are now under development by a number of international drug discovery companies using peptides and protein-based "scaffolds", such as affibodies (Affibody), darpins (Molecular Partners), affilins (Scil Proteins), anticalins (Pieris), AdNectins (Compound Therapeutics) and Kunitz domains (Dyax). According to a report from the Inaugural IBC Beyond Antibody Conference in San Diego in June 2006, most companies are focused on identifying peptide therapeutic candidates by screening libraries of random peptides, which are artificially displayed within protein-scaffolds.
While this promising approach has not yet been proven to be successful, it is likely that multiple drug candidates will emerge from this class over the next decade. However, these protein scaffolds are generally larger than even Fuzeon, precluding their synthetic manufacture. Moreover, since there are up to about 3000 basic shapes in the protein world (called "folds") some shapes of disease-associated target proteins may not be compatible with particular classes of scaffolds. Phylogica has developed a new class of drug called phylomers, sourced from libraries of peptides from ancient bacteria, which offer high levels of structural diversity and overcome some of the problems of conventional peptides and monoclonal antibodies. Phylomers are medium-size peptides of about 15 to 80 amino acids with structures that represent natural protein interfaces that have been conserved for stability through evolution. The evolutionary advantage The diversity of phylomers is huge because they come from bacterial species that have been diverging from one another for billions of years of evolution.
For example, the ancient bacterial kingdom of archea diverged from the eubacterial kingdom, to which conventional bacteria belong, more than 3 billion years ago. Phylogica's phylomer libraries are made from bacteria of both of these major kingdoms. However, the major phyla, or divisions, of plants and animals have only been around for a little over 1 billion years – mammals diverged from birds only 300 million years ago, while our earliest hominid ancestors date from only a few million years ago. In contrast to protein scaffolds, many phylomers are less than 30 amino acids in size, allowing chemical synthesis and a more straightforward regulatory route. Despite their foreign origin, many phylomers are sufficiently small to evade the "radar" of the immune system, making them even more attractive as drug candidates as it is expected that some phylomers would not require humanisation.
Phylogica's stroke candidates PYC35S and PYC36S have recently been shown in laboratory and preclinical studies to have suitable stability properties to function as stroke therapies, and its candidate PYC35B is showing promise in animal models of burns wound healing. By screening its libraries of up to 260 million phylomer peptides, Phylogica has obtained unprecedented hit rates for blocking the interactions between disease associated target proteins. This is presumably due to the enormous structural diversity present within phylomer libraries.
Phylomers represent naturally folded structures representing thousands of classes of protein shapes, as opposed to artificial distortion of random peptide structures into one class of scaffold. Therefore, having more shapes in phylomer libraries provides a greater likelihood of finding a shape which fits a given disease target. Other Australian companies are also examining the ability of naturally derived peptides to improve patient treatments.
Neuren Pharmaceuticals' lead product glypromate is a protein-fragment derived peptide, derived from insulin-like growth factor (IGF-1). Neuren Pharmaceuticals and Metabolic Pharmaceuticals are co-developing neural regeneration peptides that are able to reverse the effects of nerve damage. Similarly, Metabolic's obesity/osteoporosis drug is a peptide derived from a fragment of human growth hormone.
With advances in peptide technologies, the uses of peptides are clearly expanding outside the therapeutic area into diagnostics and cosmetics. According to a statement by US company Atrium Biotechnologies, "The rise in the popularity of peptides in cosmetics formulations is being driven by demand for efficient actives that deliver a range of functions to skin care and other cosmetics preparations." Whether or not peptides in skin care formulations can reverse the damaging effects of ageing and exposure to the elements, such cosmetic application circumvents one of the major challenges with peptides – delivering them to sites in the body at sufficient concentration and for long enough to have an effect.
Next: Advantages and challenges of peptide therapeutics
About the author Adjunct Associate Professor Paul M Watt is vice-president of technology development at biopharmaceutical drug discovery company Phylogica. His research career began at Oxford University in the area of molecular biology and bacterial and yeast genetics. After a stint at Harvard University and a second postdoctoral fellowship in yeast genetics at Oxford, he returned to his home town of Perth, where he became interested in the emerging antibody field, noting its limitation and
http://www.phylogica.com/webbox/media/BTN2.pdf
PYC Price at posting:
0.0¢ Sentiment: Buy Disclosure: Held
A personalised tool to help users track selected stocks. Delivering real-time notifications on price updates, announcements, and performance stats on each to help make informed investment decisions.
(20min delay)