Decoding Malaria's 'Post Code' System Provides A Potential Drug Target

”We have now cracked the ‘post code’ needed to do this” says Professor Geoff McFadden from the Department of Botany at the University of Melbourne.

These results could allow the design of a drug which would confuse this communication process and kill the parasite, as well as providing insight into the parasite's evolution.

The malaria parasite (Plasmodium falciparum) -having a structure similar to most animal cells- is divided up into discrete sections. Like rooms in a house these have different functions including making proteins, producing energy and the nucleus containing most of the cell’s DNA.

To make energy for its survival, malaria needs specific proteins delivered to certain sites inside its cell. “The malaria parasite makes its energy in a cell compartment called the plastid- this is a structure similar to a plant chloroplast but is not used in photosynthesis” adds Prof McFadden.

“We focused on the plastid as a parasite target because it is relatively simple and isn’t present in humans.”

Once the DNA has instructed the production of a protein, it still has to find its way back to the plastid to be used in energy generation. This is achieved by proteins having a certain 'post code' – a peptide known as a protein targeting sequence- which directs it to its destination.

”To decipher the targeting code we mutated the amino acids which make up the the targeting peptide to check which parts were essential for plastid transport and which were not.”

“We then screened these proteins for function with a computer simulation tool and also tested their actual behaviour in malaria parasites by introducing synthetic genes which coded for the mutated proteins.”

“We discovered that the malaria parasite has a developed a clever trick- to have a very general plastid targeting code, which may have enabled it to evolve faster”.

Just a positive charge in a certain place and an affinity for water is all the protein needed to find its way to its destination. If the transit peptide had these essential characteristics—no matter what order its amino acids were in, or even which ones were included—the protein could enter the plastid.

“We now have the potential to use the relative lack of sophistication in this system as a way to confound it. If we can disable the mechanism that reads the post code, we could probably stop the entry process and kill the parasite.”

Prof McFadden and colleagues then extended the study to show how loose the targeting system was by testing targeting peptides made up of strings of English words, with each of the 20 amino acids representing a different letter in the alphabet.

The computer correctly predicted that SKINNYSLINKYKINKYTHING had the essential characteristics and would get into the plastid, and ITWILLNEVERTARGETPLASTID did not and would be left outside.

“Essentially, we are able to tell the parasite what to do in our language by finding sentences with dual meaning both in English and cell biology. An algorithm initially designed to predict what the sequences do in real life has now been adapted to act as a translator between two forms of language.”

“It is well established that humans can recognise words even if the order of the letters has been scrambled.”

In tihs paepr we sohw taht jsut as mxinig up letetrs deos not sotp you form bineg albe to raed tehm, nor deos it sotp cells form 'reading' tehm.

“Our key finding is that the order of amino acids in peptides responsible for transport of proteins into the plastid of malaria parasites is not important; only the overall content matters.”

The study is published in the early on line edition of Proceedings of the National Academy of Sciences the week of March 17, 2008. It is co-authored by researchers at the Walter & Eliza Hall Institute and the Department of Botany, University of Melbourne.