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Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named "LipoGalardin" (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor.

Molecular modeling was undertaken at aims to analyze the interactions between oleic acid and human leukocyte elastase (HLE), plasmin and matrix metalloproteinase-2 (MMP-2), involved in the inhibitory capacity of fatty acid towards those proteases. The carboxylic acid group of the fatty acid was found to form a salt bridge with Arg(217) of HLE while unsaturation interacted with Phe(192) and Val(216) at the S(3) subsite, and alkyl end group occupied S(1) subsite. In keeping with the main contribution of kringle 5 domain in plasmin-oleic acid interaction [Huet E et al. Biochem Pharmacol 2004;67(4):643-54], docking computations revealed that the long alkyl chain of fatty acid inserted within an hydrophobic groove of this domain with the carboxylate forming a salt bridge with Arg(512). Finally, blind docking revealed that oleic acid could occupy both S'(1) subsite and Fn(II)(3) domain of MMP-2. Several residues involved in Fn(II)(3)/oleic acid interaction were similarly implicated in binding of this domain to collagen. Oleic acid was covalently linked to galardin (at P'(2) position): OL-GAL (CONHOH) or to its carboxylic acid counterpart: OL-GAL (COOH), with the idea to obtain potent MMP inhibitors able to also interfere with elastase and plasmin activity. OL-GALs were found less potent MMP inhibitors as compared to galardin and no selectivity for MMP-2 or MMP-9 could be demonstrated. Docking computations indicated that contrary to oleic acid, OL-GAL binds only to MMP-2 active site and surprisingly, hydroxamic acid was unable to chelate Zn, but instead forms a salt bridge with the N-terminal Tyr(110). Interestingly, oleic acid and particularly OL-GALs proved to potently inhibit MMP-13. OL-GAL was found as potent as galardin (K(i) equal to 1.8nM for OL-GAL and 1.45nM for GAL) and selectivity for that MMP was attained (2-3 log orders of difference in inhibitory potency as compared to other MMPs). Molecular modeling studies indicated that oleic acid could be accommodated within S'(1) pocket of MMP-13 with carboxylic acid chelating Zn ion. OL-GAL also occupied such pocket but hydroxamic acid did not interact with Zn but instead was located at 2.8Å from Tyr(176). Since these derivatives retained, as their oleic acid original counterpart, the capacity to inhibit the amidolytic activity of HLE and plasmin as well as to decrease HLE- and plasmin-mediated pro MMP-3 activation, they might be of therapeutic value to control proteolytic cascades in chronic inflammatory disorders., (Copyright © 2010 Elsevier Inc. All rights reserved.)