Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø, Denmark.
Department of Food Science, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg, Denmark.
Molecules. 2018 Mar 10;23(3):630. doi: 10.3390/molecules23030630.
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 -alkylglycines) provides the potential to improve stability. We have identified two novel peptoid-based compounds, and , which are effective against the canine skin pathogen , 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 and were resistant to proteases and >98% bound to plasma proteins. While half-lives in liver microsomes for both were >2 h, peptoid 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.
抗菌肽 (AMPs) 有望成为下一代抗菌药物，但在体内往往容易迅速降解。用非天然氨基酸残基如肽（- 烷基甘氨酸的低聚物）修饰 AMP ，可以提高稳定性。我们已经鉴定出两种新型的基于肽的化合物 和 ，它们对犬皮肤病原体 有效，这是伴侣动物中抗生素使用的主要原因。我们通过研究它们从制剂中的释放和体外 ADME 特性，报告了它们通过局部治疗感染的潜力。体外 ADME 测定包括皮肤渗透特性、对蛋白酶和肝微粒体的稳定性以及血浆蛋白结合。 和 都能抵抗蛋白酶，与血浆蛋白的结合率>98%。虽然两者在肝微粒体中的半衰期均>2 h，但肽-肽类杂合 B1 （>2 与 0.5 h）对血浆蛋白酶的稳定性更高。两种化合物都适合在油包水乳膏制剂中给药（8 h 释放 50%），在不存在或存在皮肤渗透增强剂的情况下，均无皮肤渗透。我们的结果表明，这些基于肽的药物可能适合作为局部治疗犬浅表脓皮病的抗菌药物，并且可以克服肽中遇到的固有稳定性限制。
