A human surfactant peptide-elastase inhibitor construct as a treatment for emphysema

Abstract

Two million Americans suffer from pulmonary emphysema, costing $2.5 billion/year and contributing to 100,000 deaths/year. Emphysema is thought to result from an imbalance between elastase and endogenous inhibitors of elastase, leading to tissue destruction and a loss of alveoli. Decades of research have still not resulted in an effective treatment other than stopping cigarette smoking, a highly addictive behavior. On the basis of our previous work, we hypothesize that small molecule inhibitors of human neutrophil elastase are ineffective because of rapid clearance from the lungs. To develop a long-acting elastase inhibitor with a lung pharmacodynamic profile that has minimal immunogenicity, we covalently linked an elastase inhibitor, similar to a trifluoro inhibitor that was used in clinical trials, to a 25-amino-acid fragment of human surfactant peptide B. We used this construct to prevent human neutrophil elastaseinduced emphysema in a rodent model. The elastase inhibitor alone, although in a 70-fold molar excess to elastase in a mixture with <0.6% residual elastase activity, provided no protection from elastase-induced emphysema. Covalently combining an endogenous peptide from the target organ with a synthetic small molecule inhibitor is a unique way of endowing an active compound with the pharmacodynamic profile needed to create in vivo efficacy.lung cancer | resistant infections | tuberculosis | asthma I nhalation is an important means of systemically delivering drugs that require immediate onset of action because the lungs provide a facile conduit to the bloodstream (1). Conversely, rapid lung clearance of small molecules causes a significant challenge for the development of pulmonary therapeutics. Rodent models of elastase-induced emphysema, for example, highlight the challenges for the development of effective drugs for pulmonary diseases. Potent in vitro human neutrophil elastase (HNE) inhibitors are cleared from the animals' lungs in minutes and may even exacerbate HNEinduced emphysema (2), whereas one intratracheally instilled dose of elastase causes maximum lung damage after 4 wk (3). The combination of long-term chronic pulmonary damage that characterizes the progression of emphysema with the rapid lung clearance (4) and potential nephrotoxicity (5) of small molecule drugs indicates that there is a profound need for new ways of producing pulmonary therapeutics with long lung residence time pharmacodynamics.Because emphysema is a chronic disease, any treatment will likely be administered over the course of the patient's life, and thus long-acting agents may induce an immune response that would negate the therapeutic effect. The ability of the treatment to access all regions of the vast lung surface area must also be considered. One way to slow the clearance of a small molecule inhibitor from the lung is to attach it to a larger polymer (6). For instance, the covalent linkage of a hydrophilic polymer to a peptidyl carbamate inhibitor increases the half-life by 100-fold in the lungs of hamsters and pro...

Neutrophil Elastase as a Target in Lung Cancer

“…As for any pulmonary therapeutics, compounds must display long residence time within lungs [114]. In that line, the covalent linkage of a synthetic elastase inhibitor to the N-terminal 1-25 amino acid residues of human surfactant B (SP-B) was shown to provide long time protection against emphysema [116]. As examples, coupling of a peptidyl carbonate inhibitor to a linear hydrophobic polymer of alpha, beta-poly [N(2hydroxyethyl)-D,L-aspartamide] or thiol-specific PEGylation of alpha-1 proteinase inhibitor considerably improved the pharmacokinetic profile of elastase inhibitors [115].…”

Neutrophil elastase inhibitors

“…To circumvent this problem, a transition state inhibitor of HNE was attached to a 25-amino acid fragment of human surfactant peptide B, yielding a construct 1 with a long lung residence time and minimal immunogenicity. Intratracheal administration of construct 1 prevented HNE-induced emphysema in a rodent model (77). In contrast, administration of the peptidyl difluoroketone inhibitor by itself failed to protect the lungs from the action of HNE.…”

Human Neutrophil Elastase Degrades SPLUNC1 and Impairs Airway Epithelial Defense against Bacteria

“…First, HNE levels are higher in COPD patients than normal subjects [6], [7]. Second, HNE exerts various deleterious effects on lung immunity and structure such as degradation of surfactant proteins and induction of emphysema [8]–[10].…”