Antimicrobial Peptoids

Background

Since the discovery of penicillin in 1928, a large range of antibiotics have been successfully developed to combat a wide variety of infections. However, resistance to these antibiotics is increasing at a remarkable rate and is becoming a serious problem, with drug resistant strains of previously treatable illnesses on the rise. Current structural classes of antibiotic compounds are becoming redundant and it is widely agreed that there is a desperate need to design, make and test new antibiotic compounds.

Peptide drugs have shown considerable promise as medicines, and investment in this area by the pharmaceutical industry continues to increase. Areas of significant interest lie in the use of stabilised or stapled α-helices, (multi)cyclic peptides and peptidomimetics, which include ‘peptoids’.

However, many peptide drugs are readily broken down in the human body - presenting drug formulation and delivery challenges. Moreover, physical properties such as water-solubility and membrane-permeability remain highly problematic. Many drugs fail in development at the pre-clinical stage due to poor physical properties and many limitations remain in developing peptide-based drugs with suitable pharmaceutical properties e.g. membrane permeability, bioavailability and water solubility. Aqueous formulation of peptides can, therefore, be non-trivial and are often formulated with excipients, surfactants and co-solvents, which may result in adverse side effects. Therefore, there is a need to improve peptidic drugs due to their inherently unfavorable pharmacokinetic properties e.g. stability, membrane permeability, bioavailability and water solubility.

Technology Overview

Peptoids are an emerging class of therapeutic agent, which are structurally very similar to peptides () but have a superior proteolytic stability in vivo when compared with standard peptide-based drugs ().

Peptoids that contain ‘lysine’ type side chains ( – see red side chain residue) are routinely seen in the literature. Some research groups have sought to improve the biological activity of peptoids by replacing the ‘lysine’ residues with ‘arginine’ analogues (conversion of the primary amine to a guanidinium group – Figure 3 blue residue). In part this change has been probed due to the fact that arginine-rich cell-penetrating peptides have been shown to have a high potential to deliver drugs into cultured cells. Recent work in the area has shown that guanidine containing peptoids translocate into the cell quicker than peptoids that only contain “lysine” (amine) type side chains.

Stage of Development

Both linear and cyclic peptoids have been demonstrated to be active against a range of Gram-positive and Gram-negative bacteria, including clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium, Pseudomonas aeruginosa and Salmonella enterica.

Also, antifungal and antiparasitic properties have been demonstrated.

Benefits

• Increased stability in vivo
• Inexpensive antibacterial treatment potential
• Refrigeration-free antibiotics
• Anti-fungal and anti-parasitic properties in addition

Applications

• Antimicrobial action
• Antibiotic use

Opportunity

Durham University is seeking expressions of interest from suitably positioned industry partners to take forward the commercial development of this technology through collaboration or licensing.