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Building a molecular lego to fight malaria and TB

The Endoc
Building a molecular

Tuberculosis and malaria are the most prevalent diseases that kill mankind today. Currently available methods and drugs are unable to stem the tide. This is why governments, the Gates Foundation, Wellcome Trust and others are investing large sums to find ways to stop or reduce their prevalence and to help develop new methods and molecules as drugs.
The battle between these pathogens and people is a colossal one. We need newer methods and drugs to kill these pathogens mycobacterium tuberculosis (Mtb) andplasmodium falciparum (and p. vivax). And the battle is literally mind over mutations.
The human mind has continuously attempted to devise novel molecules as drugs such as the fluoroquinolones, rifampicin, and artemisinin. On the other side, even though large numbers are killed by these drugs, an occasional outlier bug which does not succumb to the drug, thanks to a random “error” in its genetic sequence (mutation), survives and reproduces more of itself. Pretty soon, this drug-resistant mutant propagates to become the main strain, and the thoughtfully crafted drug is no longer effective.
It is also a battle of time scale. While we take years to create effective drugs and distribute them for everyday use, microbes take just hours and days to reproduce and propagate to billions in months. While the TB strains of just a few years ago could not survive rifampicin (which blocks the bug’s RNA making machinery, thus stopping its growth), today’s strains have evolved to find alternate paths to carry on. Similarly, with malaria, while artemisinin (the wonder drug of yesteryears) acts on the blood ingested by the parasite, “burns” it through oxidative stress and thus kills the pathogen, today’splasmodium strains have evolved with a mechanism to detoxify this oxidative stress and become artemisinin-resistant. We are thus facing hosts of multi-drug-resistant pathogens infecting us.
It is against this background that some new ideas have come about which could hopefully side-step this resistance issue. Note that the earlier drugs act on the pathogen after it enters the target cells in the body  be it blood, liver or elsewhere  and use the host machinery to grow and multiply. What if we stop the entry itself? Would that would stop the pathogen on its track and thus stop the infection?
Some minds have been thinking such a thought and carried out research towards this idea. The most recent one, published two weeks ago (on Pongal Day, 14-1-2015) in the journal Nature Communicationsis by Drs. Anand Ranganathan, Pawan Malhotra and their colleagues at the International Centre for Genetic Engineering and Biotechnology, and All India Institute of Medical Sciences, both in New Delhi, India (6:6049/DOI:10.1038/ncomms7049/www.nature.com/naurecommunications).
The group has capitalised on the idea that some molecules on the surface of cells, termed intercellular adhesion molecules (ICAMs, which are part of the immunoglobulin super-family) act as sentries, regulating the entry and adhesion of other cells, native or foreign. The molecule ICAM-1 is seen on various cell types, notably macrophages (a type of white blood cells that ingests foreign material). ICAM-4, on the other hand, is restricted to the surface of red blood cells. One can thus see that while ICAM-1 would regulate the entry and invasion by Mtb into macrophages, ICAM-4 would regulate malaria parasites likewise.
If only we could discover or invent a decoy molecule that sits at this gate, blocking the entry of Mtb, we could overcome infection by this deadly pathogen. Likewise, if we can block the entry and invasion byplasmodium into red blood cells, using a decoy molecule that binds to ICAM-4, we would have a drug against malaria. Note too that these decoys do not work after the event (like the drugs above do), but deny the unwelcome visitor the ‘visa’ to enter and do damage.
Molecular Lego pieces
To this end, the Delhi group decided to work on a novel idea that Dr Anand Ranganathan had come up with a decade ago, which he calls the “codon shuffling method” of making small protein molecules (see J. Biol. Chem. 280: 23605, 2005). This involves the use of a series of properly chosen “DNA Bricks”, each 6 bases long (two codons-long, for the cognosenti), linking them together to various lengths to produce a ‘library’ of peptide/protein molecules of various sizes and predictable shapes. This is an easy and crafty way, using these DNA bricks, to make a whole host of mini-proteins as potential drugs.
They next tested to see which members of the above library interact with ICAM-1 and with ICAM-4. Happily enough, a large peptide named M5 was found to bind strongly to both ICAM-1 and ICAM-4. They next challenged Mtb with macrophages in the presence of M5. While Mtb infects control samples efficiently, the rate dropped by 80 per cent in the M5-added samples. Likewise, when added to red blood cells, infection by the malaria parasite dropped by 80 per cent.
Actually, the codon-shuffling approach is more general and extendable to fight other pathogens too. And this approach is quite akin to Lego, the toy game with interlocking plastic bricks, which can be put together to make models of objects like buildings. While Lego is a game of pleasure, this molecular Lego opens the door for drug discovery.

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