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Nitric Oxide Signalling group - combatting septic shock

12 May 2011
Nitric oxide (NO) is well known as the driving force behind the most visible indication of male sexual excitement (that’s penile erection by the way, not funky dancing) but it also plays a major role in a diverse range of physiological and neurological phenomena: blood vessel growth, control of insulin release, propulsion of food down the digestive tract… even learning. Following the identification of nitric oxide as an important signaling molecule in mammals, NO was named ‘molecule of the decade’ in the 1980s and the Nobel prize for medicine was awarded to the scientists responsible for its discovery. Misregulation of NO production is associated with cardiovascular disease, neurodegeneration, some cancers, and inflammatory conditions including septic shock – a mass killer, causing hundreds of thousands of deaths per year.

Writing in Nature Reviews Drug Discovery, CSC Nitric Oxide Signalling Group Head James Leiper and collaborator Manasi Nandi of King’s College London outline the progress that has been made so far in targeting regulatory mechanisms of NO to treat these conditions. Crucially, they highlight a potential tissue-specific intervention that could be used to treat septic shock.

The starting point for NO is the enzyme nitric oxide synthase (NOS), which takes the amino acid arginine and in a catalytic feat of structural contortion twists the amino acid like a balloon modeller, popping off NO and leaving the molecule L-citrulline behind:

As well as normal arginine molecules inside a cell, there are also methylated arginines – products of chemical modifications of arginines on the surface of proteins [see box below]. Arginines with either one methyl chemical group or two methyls in an asymmetric arrangement lower NO production by ’tricking’ the NOS enzyme into grabbing them instead of unmethylated arginine. Their additional methyl chemical groups halt NO production. Because of this ability to halt the reaction, asymmetrically dimethylated arginine ‘ADMA’ – present at much higher levels than the monomethylated version – is considered to be the primary cellular inhibitor of NO production. ADMA is itself regulated by the enzyme DDAH, adding an additional level of NO regulation and consitituting a potential therapeutic target that has attracted considerable interest.

Proteins are messy 3D balls of amino acids linked together, full of twisted conformations and with many amino acids, including arginine, dangling from the protein's surface. These can be subject to modifications, which can alter the protein's characteristics. Methylarginines are the only by-product of these protein modifications that have an effect on metabolism.

Loss of of DDAH leads, through an increase in ADMA, to lower NO production – a state associated with cardiovascular disease and insulin resistance; high levels of DDAH and elevated NO is associated with some forms of cancer, neurodegeneration and arthritis, as well as septic shock. Pharmaceutical activation of DDAH however is not currently possible in cases of lowered NO, with gene therapy proposed as a potential alternative avenue for treatment. In situations of elevated NO such as septic shock the lack of clinically efficacious drugs prompted researchers to manipulate the NO-ADMA-DDAH system itself by administering large doses of monomethylated arginine. While this treatment was found to reduce septic shock from NO, it interfered with normal cellular NO signalling, a side-effect with potentially lethal consequences.

James Leiper’s group have developed synthetic mimics of arginine that inhibit DDAH in order to sidestep this problem. In rodents, these molecules have been shown to interact with only one particular form of DDAH (DDAH1) lowering NO associated with septic shock but leaving normal cellular NO signalling intact. The authors stress the importance of moving sthese findings wiftly towards preclinical development and then clinical trials.

Says Leiper, “in addition to giving us a greater understanding of the DDAH-ADMA-NO system, these findings have helped us to identify an important therapeutic target for septic shock…a condition that still kills hundreds of thousands of people each year”.

This work was published in Nature Reviews Drug Discovery.

Leiper, J., Nandi, M. (2011). The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nature Reviews Drug Discovery 10, 277–291.

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