Prof Arthur Christopoulos

Position

Professor of Pharmacology
Faculty of Pharmacy and Pharmaceutical Sciences

NHMRC Principal Research Fellow

Theme Leader - Drug Discovery Biology
Monash Institute of Pharmaceutical Sciences

An end to ‘blunt hammer’ medicines

Professor Arthur Christopoulos is working to end the reign of "blunt hammer" medicines. By targeting previously unappreciated drug recognition sites in the body, Arthur and his colleagues are developing medicines potent enough to offer better treatment of schizophrenia and diabetes, and selective enough to eliminate side-effects.

Key to the research at the Monash Drug Discovery Biology Laboratory is understanding the potential of “allosteric” sites on G protein-coupled receptors (GPCRs), the largest drug target family in the human genome.

These GPCR allosteric sites have largely been ignored in traditional drug discovery approaches, but offer tremendous opportunity for researchers who can understand and exploit them.

"Nearly all drugs do one of two things - they either block something or they mimic something," Arthur says.

"But what they block and mimic are the body's own chemicals, which interact with highly conserved regions on the GPCRs.  What we have found is that GPCRs have other, more variable, sites where the body's chemicals don't act, and we can make synthetic chemicals that target those other sites.

"In terms of the old ‘lock and the key’ view of how drugs work, we have basically found alternative, more flexible, locks," Arthur says.

Increasing drug selectivity is vital to eliminating medication side-effects.

Drugs that block or mimic the body's chemicals will act wherever those chemicals are found. So, if a drug is designed to target the body’s chemical site in a brain protein, it may also act in the same region of the same protein in the heart. These are the "blunt hammers" Arthur is trying to eradicate.

In addition to reducing side-effects, targeting allosteric sites offers better ways of treating cognitive deficits in schizophrenia.

"One of the biggest problems with treating schizophrenia is that the anti-psychotic drugs on the market will treat the psychotic symptoms very well, but what they don’t treat well are the so-called negative symptoms, such as withdrawal or apathy, or the cognitive memory effects" Arthur says.

"It's an unmet medical need we are trying to fill. And we have found allosteric sites that are very selective to a family of proteins in the brain that have positive cognitive effects."

Arthur's work could also have positive consequences for adult-onset diabetes sufferers, potentially eliminating the need for regular injections.

Allosteric small-molecule compounds offer the potential for orally available tablets to reach the key diabetes drug targets currently only accessible with larger (injectible) peptides.

It is potential break-throughs like this that led Arthur into pharmacology research.

"I originally trained as a pharmacist, and I was working in a pharmacy while completing my PhD," he says.

"I saw at the front end what medications were available and, for many diseases, they’re just not good enough. We are giving blunt hammers to the elderly who are particularly sensitive to the side effects of these medications, and our population is ageing, getting obese and more diabetic as well, so any way we can fine tune medications will be great for society.

"Now is the time for Monash to say we can contribute here, we can really turn our discoveries into something."