Danijel Kikelj

Modifying those Molecules

Small, smaller, smallest: that, in a nutshell, is the concept behind muramyl dipeptides (MDP), the smallest immuno-stimulatory fragments of a bacterial cell wall. But despite their tiny size, they are highly crucial for detecting infections in our bodies – infections ranging from tuberculosis to HIV/AIDS.

Although MDP have undisputed qualities as natural therapeutic microorganisms, there is a price to pay in so far as their side-effects very often make them unsuitable to treat a number of illnesses.

That was to change in 1994, when a team of Slovenian scientists at the University of Ljubljana in Slovenia, along with Ljubljana-based pharmaceutical company LEK, filed a patent on so-called novel heterocyclic acyldipeptides (patent published July 1, 1998). Essentially, these are derivatives and analogues of MDP that possess strong biological activity and have strong immuno-stimulatory and anti-tumour effects.

“The immuno-stimulants were known, so the idea was to produce a new compound with the same positive effects while cutting out some of the side-effects,” said Danijel Kikelj, one of the patent’s inventors. Kikelj is a professor in pharmaceutical chemistry at the University of Ljubljana.

He and his co-inventors figured out that the trick was to find a replacement for the sugar part of the molecule, a common procedure in medicinal chemistry.

“The essential aim and challenge was to modify the molecule to see what would happen,” said Kilkelj. “We wanted to produce a molecule that mimics the sugar part of the MDP compound, but at the same time retain the anti-tumour activity.”

The invention specifically targets cancer. Despite significant efforts to find new approaches for treating the disease, the primary options remain surgery, chemotherapy and radiation therapy, used separately or in combination.

Surgery and radiation therapy, however, are generally useful only for fairly defined types of cancer. Chemotherapy is the method that is generally useful in treating patients with metastatic cancer or cancers such as leukaemia.

Although chemotherapy can provide a therapeutic benefit, it often fails to result in the cure of the disease due to the patient's cancer cells becoming resistant to the chemotherapeutic agent.

Working on assumptions similar to those of Kikelj, scientists at the Clinical Research Institute of the National Kyushu Cancer Centre, Fukuoka in Japan, discovered a need for additional chemotherapeutics, anti-microbial agents and anti-inflammatory agents to treat cancer, inflammatory diseases and infectious diseases.

Despite the progress made in this field, Kikelj says the owner of the patent, LEK, decided not to proceed with turning the patent into a commercially-viable drug for a host of reasons. He added that countless patents are never developed into a marketable product. This was the case in Europe with this particular patent.

In Japan, by contrast, Japanese pharmaceutical company Daiichi launched a drug called Romurtide in 1991, which has been quite successful in its use as an anti-tumour agent. Kikelj, who earned his PhD in pharmaceutical chemistry at the University of Heidelberg in Germany, is not disheartened by the fact that in this particular instance there was no commercial product resulting from the research here in Europe. He said the fruits of his team’s labour are manifold.

“It was a great team effort from the university, and we enjoyed important financial and infrastructural support from LEK. The benefits of our work can be seen and used in related anti-tumour and anti-viral products.”