ESF Eurocores SONS Project NanoSMAP

The Drug Development Process

The process of finding new pharmaceutical drugs is long and rather complicated, which is a major reason why many drugs are so expensive. To begin with, researchers must identify what mechanisms cause a certain disease. This step is called target identification, as the goal is to find out exactly what should be target by the drug and in what way. Today, more than 50% of all drug targets are membrane proteins. If a membrane protein is compromised or damaged in some way, this may lead to a number of problems such as

- faulty signals between cells (too strong a signal, no signal, or wrong signal)

- faulty cell recognition (cells cannot identify each other correctly)

- problems related to the transport of nutrients, ions and/or water in and out of cells

and this might in turn lead to disease. Thus, current research focuses on understanding the exact workings of the various membrane proteins. By finding substances that block, enhance or otherwise manages cell signals or nutrient, ion and water transport in and out of cells, pharmaceutical companies are able to create drugs that act specifically on the membrane proteins in question.

The process of finding substances that act in a certain way on particular membrane proteins is called lead identification and that is the next step of the drug development process. In this step, highly accurate and specific screening methods are required to identify active substances (leads) which bind to a pre-selected drug target and have the desired therapeutic effect. An assessment of the potential adverse effects of the active substances must also be made at this stage. This is done through high throughput screening, an automated process where thousands of compounds are tested for their effects on the target protein.

While there mya be thousands of compounds tested during HTS, only a fraction of those will qualify for further testing. This next step is called lead optimization and involves changing the compounds so that their effect is enhanced. For example, this may involve steps to ensure that the drug is delivered immediately to those particular membrane proteins in a certain part of the body that needs to be targeted. Since the body's response to any foreign subtances is to try to break these down and eliminate them, the lead optimization phase is also about making sure the compounds have effect for long enough to achieve their intended therapeutic mission. The lead optimization phase involves animal testing, and the results from these tests are used to decide which substances will make it on to clinical trials (tests on humans).

The last step of the drug development process involves clinical trials, where prototypes of the final pharmaceutical drug is tested on humans.

ASMENA's Impact on Future Drug Development

The drug development process is time-consumimg and costly, and still the absolute safety of the drugs developmed can never be 100% guaranteed. Thus, there is a strong demand for screeening methods that would shorten and cheapen the process, while at the same time generate more accurate screening results. The ASMENA project is expected to make an important contribution to future drug screeening and to the knowledge of membrane proteins.

There are several problems associated with the lead identification phase, making it the bottleneck in the drug development process. For example, current drug screening assays targeting membrane proteins rely to a large extent on fluorescent recording. This means that the lead substances tested are "labeled" with a fluorescent compound in order for researchers to be able to check the effect of that substance. However, labels are an unnatural attachment or component to the molecule to be investigated and may affect its biochemical behaviour. In the worst case this leads to false readouts. Of the few existing label free methods available, all suffer from low throughput and, in certain cases, low information content. Thus, there is a strong desire to transfer fluorescent recording into high throughput, label-free formats with great information content. There is also a high demand to measure functions of membrane proteins which are highly diverse.

The ASMENA project aims to develop the knowledge and methods needed to build label-free array formats for membrane protein screening assays. By downscaling assays, costs can be reduced by reducing reagent consumption and substance use, and also by allowing earlier detection of drugs hits or toxicity effects. Combining several such assays on a chip will create a versatile platform where a great number of events can be measured at the same time at diffeent spots on the chip, enabling functional screening of drug interactions with membranes and several classes of membrane proteins, which are potential drug targets. The primary use of the developed technology will be for analytical profiling, which is the reliability step before screening in drug lead discovery.

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