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Molecules 2018, 23(3), 630; https://doi.org/10.3390/molecules23030630

In Vitro ADME Properties of Two Novel Antimicrobial Peptoid-Based Compounds as Potential Agents against Canine Pyoderma

1
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
2
Department of Food Science, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg, Denmark
3
Zoetis Inc., 333 Portage St., Kalamazoo, MI 49007, USA
4
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark
5
Department of Veterinary and Animal Sciences, University of Copenhagen, Stigbøjlen 4, 1870 Frederiksberg C, Denmark
*
Authors to whom correspondence should be addressed.
Received: 17 January 2018 / Revised: 28 February 2018 / Accepted: 5 March 2018 / Published: 10 March 2018
(This article belongs to the Special Issue Antimicrobial Peptides and Peptidomimetics)
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Abstract

Antimicrobial peptides (AMPs) hold promise as the next generation of antimicrobial agents, but often suffer from rapid degradation in vivo. Modifying AMPs with non-proteinogenic residues such as peptoids (oligomers of N-alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, B1 and D2, which are effective against the canine skin pathogen Staphylococcus pseudintermedius, the main cause of antibiotic use in companion animals. We report on their potential to treat infections topically by characterizing their release from formulation and in vitro ADME properties. In vitro ADME assays included skin penetration profiles, stability to proteases and liver microsomes, and plasma protein binding. Both B1 and D2 were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid D2 showed higher stability to plasma proteases than the peptide-peptoid hybrid B1 (>2 versus 0.5 h). Both compounds were suitable for administration in an oil-in-water cream formulation (50% release in 8 h), and displayed no skin permeation, in the absence or presence of skin permeability modifiers. Our results indicate that these peptoid-based drugs may be suitable as antimicrobials for local treatment of canine superficial pyoderma and that they can overcome the inherent limitations of stability encountered in peptides. View Full-Text
Keywords: antimicrobial peptoids; peptidomimetics; in vitro ADME; topical formulation; metabolic stability antimicrobial peptoids; peptidomimetics; in vitro ADME; topical formulation; metabolic stability
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Greco, I.; Hummel, B.D.; Vasir, J.; Watts, J.L.; Koch, J.; Hansen, J.E.; Nielsen, H.M.; Damborg, P.; Hansen, P.R. In Vitro ADME Properties of Two Novel Antimicrobial Peptoid-Based Compounds as Potential Agents against Canine Pyoderma. Molecules 2018, 23, 630.

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