cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.

英国呼吸系统疾病的死亡率是欧盟平均水平的两倍，NHS的成本比其他任何疾病地区都高。慢性阻塞性肺病是世界上第四大死因，在英国每年造成约26,000人死亡，约1,500人死于哮喘。这种衰弱的疾病与慢性炎症引起的肺损伤有关，慢性炎症是由于“炎症”细胞的持续激活造成的。提高这些细胞内一种名为cAMP的物质的水平，可以阻止这种情况发生。这样做的一个有效方法是阻止cAMP被PDE4酶分解。目前，科学家已经制造出与PDE4上的“嘴”紧密结合的抑制分子，在那里cAMP被消化，阻止它分解cAMP。然而，将这些用作药物的一个主要问题是副作用，如恶心和呕吐。现在很清楚的是，有一个很大的PDE4酶家族，其中只有某些酶在细胞中发现，导致肺部炎症和损伤。我们的目标是确定特定的PDE4酶，抑制这些酶对于阻止损伤和帮助修复肺是重要的。然后，我们需要设计方法，有选择地抑制这些药物，而不是所有的PDE4，以生产没有副作用的药物。由于所有PDE4酶都有相同的嘴来消化cAMP，我们需要采取一种新的方法来仅抑制关键的PDE4。要做到这一点，我们将利用我们的发现，即单个PDE4内置了独特的“邮政编码”。这些POST代码允许特定的PDE4定位到细胞内的正确位置，以便它们正常工作。这是因为单个邮政编码被放置在细胞中具有战略意义的重要位置的不同锚定蛋白识别。这种针对正确地点的目标对于特定的PDE4完成他们的工作是至关重要的。我们的目标是确定PDE4的锚蛋白和相关的邮编码子，我们需要抑制它们来阻止炎症和肺损伤。然后，当我们完成这项工作时，我们将设计分子来阻止关键PDE4的邮政编码被它们的锚识别。这些分子将阻止PDE4进入细胞中有助于炎症发生的地方。这些应该提供了一种治疗COPD的药物制造的新方法，我们预计这种方法不会受到目前正在开发的药物造成的副作用。

The death rate from respiratory diseases in the UK is twice the EU average and costs the NHS more than any other disease area. Chronic Obstructive Pulmonary Disease, the fourth leading cause of death in the world, causes around 26,000 deaths/year and asthma around 1500 deaths/yr in the UK. This debilitating illness is associated with lung damage caused by chronic inflammation due to the sustained activation of 'inflammatory' cells. Raising the levels of a substance called cAMP, inside these cells, can stop this. An effective way of doing this is to stop cAMP from being broken down by PDE4 enzymes. At the moment scientists have made inhibitor molecules that bind tightly to the 'mouth' on PDE4 where cAMP is digested, stopping it breaking down cAMP. However, a major problem using these as medicines are side-effects like nausea and vomiting. It's now clear that there is a large family of PDE4 enzymes where only certain of these are found in cells causing inflammation and damage in lungs. We aim to identify the particular PDE4 enzymes that it is important to inhibit in order to stop damage and help repair lungs. Then we need to devise ways to inhibit these selectively, rather than all PDE4s, to produce medicines without side-effects. As all PDE4 enzymes have identical mouths for digesting cAMP we need to take a new approach to inhibit just the critical PDE4s. To do this we will exploit our discovery that individual PDE4s have unique 'postcodes' built into them. These post-codes allow particular PDE4s to be targeted to the right place inside cells for them to work properly. This happens because the individual postcode is recognised by distinct anchor proteins placed at strategically important sites in cells. This targeting to exactly the right place is essential for particular PDE4s to do their job. We aim to identify anchor proteins and relevant postcodes for the PDE4s that we need to inhibit to stop inflammation and lung damage. Then, when we've done this, we will design molecules that stop the postcode of critical PDE4s from being recognised by their anchors. These molecules will prevent PDE4s from going to the place in the cell where they help inflammation to occur. These should provide a new way of making medicines to treat COPD that we anticipate will not suffer side effects caused by medicines currently being developed.