Dompe researchers develop chemokine receptor CXCR1 antagonist for the prevention of acute transplant rejection, chronic ischemic conditions and inflammatory disorders

DailyUpdates 31st August, 2004: Organ transplantation is now common with over 22,000 procedures performed in the in 2001; the most commonly transplanted organs being the kidney, liver and heart. The large numbers of transplants now being conducted is due in part to the ability of immunomodulatory agents to control acute rejection.

Delayed graft function, caused by ischemia-reperfusion injury, and host vs graft reaction are the principal mechanisms of acute rejection after transplantation. The use of immunosuppressants has successfully combated acute rejection and the allograft commonly survives for prolonged periods, even though immunosuppressive drug dosages are reduced to very low levels. Currently employed immunosuppressants suppress all immunologic reactions, thus making overwhelming infection the leading cause of death in transplant recipients. In addition immunosuppressants are associated with severe toxicity.

The most significant complications of drugs used for transplant patients include nephrotoxicity, neurotoxicity, new-onset post-transplant diabetes mellitus, hyperlipidemia, and hypertension. These side effects occur in part because of the ubiquitous expression of the molecular targets of currently used immunosuppressants. New clinical options are however on the horizon and will hopefully offer immunosuppression with fewer adverse effects than current agents. In particular the development of therapeutic strategies that are able to specifically target ischemia-reperfusion injury and the subsequent infiltration of mononuclear cells, a primary cause of acute rejection, would be of benefit. This is especially true for marginal organs.

Marginal organs are taken from people who had high blood pressure or other health problems, as well as organs from non-heart beating donors. These marginal organs once were presumed to have higher failures rates, but research now suggests that the majority of them fare as well as any other transplanted organ. Organ transplant ischemia-reperfusion affects 20-30% of cadaver-donor kidneys, and its rate may rise as more organs are removed from marginal donors. The use of marginal organs as a donor alternative is becomming increasingly frequent however exploiting the full potential of this source of grafts will require improved options for the prevention of delayed graft function.

Leukocyte trafficking into tissue sites of inflammation is directed by chemokines. Chemokines are grouped into four families. Human CXC ligand 8 (CXCL8)/IL-8 and related molecules are polymorphonuclear cell chemoattractants. Two high-affinity human CXCL8 receptors are known, CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). By recruiting and activating polymorphonuclear cells, CXCL8 and related rodent molecules have been implicated in a wide range of disease states characterized by polymorphonuclear infiltration in organs, including reperfusion injury. In this month's edition of the journal PNAS, researchers from describe the development of a CXCR1/CXCR2 antagonist that potently inhibits the infiltration of polymorphonuclear cells.

The NSAIDs (R)- and (S)-ketoprofen are able to prevent the infiltration of polymorphonuclear cells independent of their cyclooxygenase inhibitory activity and the authors suggest that this results from the binding of these molecules to a common molecular structure on both the cyclooxygenase enzyme and the CXC receptor. Ketoprofen was used therefore as a starting point in a molecular modelling study that resulted in the identification of repertaxin, a therapeutic candidate that inhibited human polymorphonuclear migration induced by CXCL8 with nanomolar potency. This was suggested to reflect potent noncompetitive allosteric inhibition of the CXCR1 receptor and less potent antagonism of CXCR2.

Cecal ligation and puncture results in peritoneal infiltration of polymorphonuclear cells and in addition to being a model of sepsis is frequently used to evaluation the efficacy of agents designed to prevent neutrophil migration. Repertaxin effectively inhibited the infiltration of neutrophils in this model. Furthermore at doses as low as 3mg/kg repertaxin inhibited polymorphonuclear cell recruitment into reperfused livers, almost abolishing infiltration at 15mg/kg, and drastically reducing liver damage.

EU and US authorities have granted orphan drug status to repertaxin for the prevention of delayed graft function in organ transplantation. Subsequently three Phase I studies of repertaxin were completed. In a double-blind, placebo-controlled trial, an iv infusion of repertaxin was found to be well tolerated but had a very short half life.

In addition to improving transplant success, the development of molecules that inhibit polymorphonuclear migration are expected to be of considerable benefit for the treatment of other more chronic inflammatory and ischemic conditions.

A recent report has underlined the lack of therapeutic options for the frequent, serious and under-treated condition, peripheral artery disease. Up to 20 million Americans may suffer from this condition which often progresses to critical limb ischemia. Claudication drugs currently represent $0.4 billion in sales, a figure that could increase by as much as 6-fold with improved awareness and treatment of peripheral artery disease.

In 2001, the number of prevalent cases of IBD was been estimated to have totaled over 1.5 million in the major pharmaceutical markets. Currently in excess of $0.5 billion, IBD related sales have been forcasted to increase by 3-10% each year for the next 5 years (for more information on IBD click here or here).

Repertaxin or its analogues could be of considerable use to the treatment of these conditions and indeed second generation analogues of repertaxin are currently in development for the treatment of IBD following the conclusion of studies demonstrating the efficacy of repertaxin in an animal model of ulcerative colitis.

Source: Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury. Proc Natl Acad Sci U S A. 2004 Jul 28 [Epub ahead of print]

This article is highlighted in the August 31st edition of DailyUpdates-Inflammatory Disorders, LeadDiscovery’s unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today’s bulletin click here