Aberdeen Chemical EnterprisesYou have been contracted by Aberdeen Chemical Enterprises (ACE Ltd) to generate a new medicine to treat an immune disorder that is poorly treated by current drugs.

ACE Ltd has identified a critical protein involved in causing the disease. Blocking the action of this protein may alleviate symptoms of the disease, but there is a catch. The protein has more than one possible target site, and it is not clear which one needs to be blocked to have a therapeutic effect.

How Medicines Work

In many diseases something has gone wrong with a protein essential for healthy functioning of the human body. One way to treat diseases is to use medicines to block the malfunctioning protein and prevent its detrimental effects.

Protein

Large proteinWe often think of protein as one of the basic food groups, contained in products such as meat, fish, eggs, beans and dairy foods. The truth is that proteins are the building blocks of life. A large part of each one of us is made of protein, and proteins play many roles in our bodies ranging from the protection provided by our skin to the sending of signals to regulate our blood sugar.

They are also critical to many processes that keep us alive, such as the conversion of sugar to energy and the making of messenger molecules in the brain.

 

Malfunction

In many diseases there may be too much, or too little of a protein critical for normal function, or it may have an error in its construction. Malfunction of this protein may interfere with an important process in the body and cause disease.

Some people lack an enzyme called phenylalanine hydroxylase meaning they cannot process phenylalanine, an essential amino acid, resulting in the disease phenylketonuria which causes mental retardation.

Symptoms can be alleviated by avoiding foods rich in phenylalanine (hence the label ‘source of phenylalanine’).

Gum

 

Medicines

One way to treat diseases is to use medicines to block the malfunctioning protein and prevent its detrimental effects. For instance, statins block the effect of a protein the body uses to make cholesterol, thus reducing hardening of arteries and heart disease. The protein involved has an active site – essentially a pocket needed to make cholesterol – into which the statin fits so that less cholesterol will be made. This idea is often called the ‘lock and key’ model where the lock is the protein and the key that opens it is in this case is the cholesterol. By making a key that fits the lock, but cannot open it, such as a statin molecule, formation of excess cholesterol can be prevented. Sometimes the ‘key’ is flexible and adapts to fit the ‘lock’ to block it, a process known as ‘induced fit’.

Some processes in the human body, such as those in the immune system, rely instead on the interaction between two proteins. This means that instead of blocking a ‘lock’, two massive proteins have to be stopped from meeting. To do this, much larger medicines are needed than normally used for the ‘lock and key’ model.Lock and key

From Bugs to Drugs

For cancer and infections almost 70% of medicines come from natural sources. The search for new medicines from nature continues and has extended to include marine invertebrates such as sponges, seasquirts and soft corals.

Natuural Medicine

For cancer and infections almost 70% of medicines come from natural sources. We are all familiar with penicillin to treat infections and many of us will have heard of taxol, derived from the yew tree, to treat breast cancer.

The search for new medicines from nature continues and has extended to include marine invertebrates such as sponges, seasquirts and soft corals. Yondelis, a drug to treat a rare, previously untreatable type of cancer, is derived from a Caribbean seasquirt.

Marine invertebrates

 

Bugs?

Marine invertebrates often contain microorganisms (‘bugs’) such as bacteria and blue-green algae which produce a range of natural compounds that help defend it against predation, overgrowth and infection.

These compounds can be useful sources of new medicines, but often the microorganism cannot be grown on its own to produce the compound.This means other ways have to be found to produce these potential drugs.

The image shows an electron microscope image of the seasquirt Lissoclinum patella which contains the blue-green alga Prochloron.

Lissoclinum micrograph

 

Biotechnology

The microorganism’s DNA contains instructions to produce proteins that form the compound. Using modern biotechnology techniques we can capture this DNA and splice it into a microorganism that is easy to grow.

Growing this modified microorganism generates the proteins that can in turn produce the compounds of interest.

DNAMolecule

 

Our Work

We have been working with the Indo-Pacific seasquirt Lissoclinum patella which contains the blue-green alga Prochloron didemni which produces compounds called the patellamides.

These compounds are able to block a pump that exports cancer drugs from cancer cells when patients become resistant to chemotherapy. It is believed that blocking this pump may make other cancer treatments more effective. By re-engineering the DNA involved in making these compounds and placing it into the easy-to-grow bacterium E. coli, we can generate large quantities of the proteins which we then use to make the compounds we are interested in.

The process is also cleaner, greener and faster than the comparable chemical process.

In vitro synthesis