Pegylation of antimicrobial peptides maintains the active peptide conformation, model membrane interactions, and antimicrobial activity while improving lung tissue biocompatibility following airway delivery.
Morris. Christopher J CJ; Beck. Konrad K; Fox. Marc A MA; Ulaeto. David D; Clark. Graeme C GC; Gumbleton. Mark M
Key Findings
- PEG‑CaLL retains strong antimicrobial activity (only 2‑3× higher IC50 than unmodified CaLL) even in lung lining fluid.
- Pegylation prevents lung epithelial toxicity and pulmonary edema in an ex‑vivo rat lung model.
- Both PEG‑CaLL and regular CaLL show <3% systemic absorption after airway delivery, concentrating in lung tissue.
Practical Outcomes
- For anyone considering inhaled peptide therapies, attaching a PEG group can make the peptide much safer for lung tissue while still fighting bacteria. This suggests that plain LL‑37 or similar peptides might irritate the lungs, so a PEG‑modified version is preferable. However, creating PEG‑linked peptides requires specialized chemistry, so the insight is mainly useful for guiding product selection or future DIY formulation attempts.
Summary
Adding a polyethylene glycol (PEG) tag to the antimicrobial peptide CaLL – a hybrid of LL‑37 and cecropin A – keeps most of its ability to kill lung‑infecting bacteria while dramatically lowering the damage it can cause to lung cells. In rat lung experiments, the PEG‑tagged version didn't break the lung barrier or cause edema, unlike the unmodified peptide. Both forms stay mostly in the lung and aren't absorbed into the bloodstream, which is good for targeting infections there.
Abstract
Antimicrobial peptides (AMPs) have therapeutic potential, particularly for localized infections such as those of the lung. Here we show that airway administration of a pegylated AMP minimizes lung tissue toxicity while nevertheless maintaining antimicrobial activity. CaLL, a potent synthetic AMP (KWKLFKKIFKRIVQRIKDFLR) comprising fragments of LL-37 and cecropin A peptides, was N-terminally pegylated (PEG-CaLL). PEG-CaLL derivatives retained significant antimicrobial activity (50% inhibitory concentrations [IC(50)s] 2- to 3-fold higher than those of CaLL) against bacterial lung pathogens even in the presence of lung lining fluid. Circular dichroism and fluorescence spectroscopy confirmed that conformational changes associated with the binding of CaLL to model microbial membranes were not disrupted by pegylation. Pegylation of CaLL reduced AMP-elicited cell toxicity as measured using in vitro lung epithelial primary cell cultures. Further, in a fully intact ex vivo isolated perfused rat lung (IPRL) model, airway-administered PEG-CaLL did not result in disruption of the pulmonary epithelial barrier, whereas CaLL caused an immediate loss of membrane integrity leading to pulmonary edema. All AMPs (CaLL, PEG-CaLL, LL-37, cecropin A) delivered to the lung by airway administration showed limited (<3%) pulmonary absorption in the IPRL with extensive AMP accumulation in lung tissue itself, a characteristic anticipated to be beneficial for the treatment of pulmonary infections. We conclude that pegylation may present a means of improving the lung biocompatibility of AMPs designed for the treatment of pulmonary infections.
Study Information
pubmed
2012
2012-03-19T00:00:00.000Z
10.1128/aac.06335-11