In Vivo Biodistribution and Small Animal PET of ⁶⁴Cu-Labeled Antimicrobial Peptoids

Abstract

Peptoids are a rapidly developing class of biomimetic polymers based on oligo-N-substituted glycine backbones, designed to mimic peptides and proteins. Inspired by natural antimicrobial peptides, a group of cationic amphipathic peptoids has been successfully discovered with a potent and broad-spectrum activity against pathogenic bacteria; however, there are limited studies to address the in vivo pharmacokinetics of the peptoids. Herein, 64Cu labeled DOTA conjugates of three different peptoids and two control peptides were synthesized and assayed in vivo by both biodistribution studies and small animal positron emission tomography (PET). The study was designed in a way to assess how structural differences of the peptidomimetics affect in vivo pharmacokinetics. As amphipathic molecules, major uptake of the peptoids occurred at the liver. Increased kidney uptake was observed by deleting one hydrophobic residue in the peptoid, and 64Cu-3 achieved the highest kidney uptake of all the conjugates tested in this study. In comparison to peptides, our data indicated that peptoids had general in vivo properties of higher tissue accumulation, slower elimination, and higher in vivo stability. Different administration routes (intravenous, intraperitoneal, and oral) were investigated with peptoids. When administered orally, the peptoids showed poor bioavailability, reminiscent to that of peptide. But, remarkably longer passage through the gastrointestinal (GI) tract without rapid digestion was observed for peptoids. These unique in vivo properties of peptoids were rationalized by efficient cellular membrane permeability and protease resistance of peptoids. The results observed in the biodistribution studies could be confirmed by the PET imaging, which provides a reliable way to evaluate in vivo pharmacokinetic properties of peptoids noninvasively and in real time. The pharmacokinetic data presented here can provide an insight for further development of the antimicrobial peptoids as pharmaceuticals.

An overview of peptide and peptoid foldamers in medicinal chemistry

“…Following oral administration, the peptoids were poorly absorbed, while their markedly slower degradation was observed in the gastrointestinal tract. These results support the view that gastrointestinal infections might be treated efficiently with peptoid antibacterials [41].…”

“…Cu-labeled peptoids and their a-peptide analogs were synthetized and administered intravenously. The liver plays a crucial role in the metabolization of amphipathic oligomers as a marked liver uptake was observed [41]. The deletion of one hydrophobic residue resulted in significant elimination through the kidneys.…”

Investigating the Anti‐leishmanial Effects of Linear Peptoids

“…[9] In contrast, the peptide-mimicking peptoids offer a significantly better opportunity for development from bench to market. [11,[12][13][14][15] Their antibacterial activity against a range of Gram-positive and Gram-negative bacteria (including MRSA), selectivity for bacterial cells, and low hemolytic activity are similar to the values reported for leading AMPs. [11,[12][13][14][15] Their antibacterial activity against a range of Gram-positive and Gram-negative bacteria (including MRSA), selectivity for bacterial cells, and low hemolytic activity are similar to the values reported for leading AMPs.…”

Helical side chain chemistry of a peptoid‐based SP‐C analogue: Balancing structural rigidity and biomimicry

“…While the fate of these mimics in the lung has yet to be established, prior work on helical, amphipathic, antimicrobial peptoids used in vivo to treat an intraperitoneal infection demonstrated that these peptoids were well‐tolerated (i.e., no apparent acute negative effects and no apparent immune response) . Similarly, 64 Cu‐labeled antimicrobial peptoids when delivered systemically per oral, intravenously, or intraperitoneally generally exhibited higher in vivo stability and tissue accumulation and slower elimination in comparison to peptides . Although we expect that our peptoid mimics will be more resistant to protease degradation compared to peptides, further studies are needed to determine in vivo fate of the entire lipid‐peptoid complex; similar to a recent carbon 13‐labeled DPPC study comparing the in vivo metabolism of poractant alfa to a synthetic, peptide‐based surfactant, CHF5633 .…”