The Structural Basis for the Prevention of Nonsteroidal Antiinflammatory Drug-Induced Gastrointestinal Tract Damage by the C-Lobe of Bovine Colostrum Lactoferrin

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs), due to their good efficacy in the treatment of pain, inflammation, and fever, are among the most prescribed class of medicines in the world. The main drawback of NSAIDs is that they induce gastric complications such as peptic ulceration and injury to the intestine. Four NSAIDs, indomethacin, diclofenac, aspirin, and ibuprofen were selected to induce gastropathy in mouse models. It was found that the addition of C-terminal half of bovine lactoferrin (C-lobe) reversed the NSAID-induced injuries to the extent of 47-70% whereas the coadministration of C-lobe prevented it significantly. The C-lobe was prepared proteolytically using serine proteases. The binding studies of C-lobe with NSAIDs showed that these compounds bind to C-lobe with affinities ranging from 2.6 to 4.8 x 10(-4) M. The complexes of C-lobe were prepared with the above four NSAIDs. All four complexes were crystallized and their detailed three-dimensional structures were determined using x-ray crystallographic method. The structures showed that all the four NSAID molecules bound to C-lobe at the newly identified ligand binding site in C-lobe that is formed involving two alpha-helices, alpha10 and alpha11. The ligand binding site is separated from the well known iron binding site by the longest and the most stable beta-strand, betaj, in the structure. Similar results were also obtained with the full length lactoferrin molecule. This novel, to our knowledge, binding site in C-lobe of lactoferrin shows a good complementarity for the acidic and lipophilic compounds such as NSAIDs. We believe this indicates that C-lobe of lactoferrin can be exploited for the prevention of NSAID-induced gastropathy.

Halogen Bonding in Supramolecular Chemistry

“…A similar water bridge is observed in the complex of diclofenac with lactoferrin, in which the water molecule was bridged between the ligand chlorine atom and the carbonyl oxygen of Val591 (Figure 78c). 317 As has been demonstrated in a nonbiological context, 51a the strength of a halogen bond can be tuned by varying the electron-withdrawing substituents on the halogen-bond donor scaffold. Hobza and co-workers have recently systematically studied the binding of bromo-and iodobenzene-derived inhibitors of aldose reductase.…”

Expression, purification, and breast cancer cell inhibiting effect of recombinant human lactoferrin C-lobe

“…Lactoferricin can also act against cancer cells via a non-receptor-mediated pathway, resulting in lysis of tumor cells. [17][18][19] Recent reports suggest that LTF C-lobe also exhibits multiple functions in vivo. For instances, the C-lobe of bovine LTF (boLTF) is protective against various disorders including gastropathy, 18) diabetes, 19) and corneal wounds and injuries.…”

Specific interactions of C-terminal half (C-lobe) of lactoferrin protein with edible sugars: Binding and structural studies with implications on diabetes

“…This cleft is particularly favorable for binding to molecules such as sugars and NSAIDs [18]. Since the size of the cleft is larger (16 Å × 8 Å) than the size of various mono-sugars, they can be accommodated easily in the binding cleft with moderate affinity without hindrance.…”