'Superdrug' Could Fight Both HIV and Malaria

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othhivandmalaria

HIV, the pandemic virus that causes AIDS, kills 2 million people each year

worldwide. Malaria, a pervasive parasite spread by mosquitoes, infects 225

million people and kills 781,000 annually. The former disease has ravaged our

species since spreading to us from monkeys a mere 40 years ago; the latter has

been our enemy for so long, our bodies have evolved ways to fight it.

The two killers, new and old, actually have a few molecular similarities.

Because of this — and some brand-new research — a single " superdrug " could soon

fight both.

That drug is HIV protease inhibitor, a medicine that scientists designed

specifically to treat HIV by preventing the deadly virus from constructing its

proteins correctly. " HIV protease inhibitors are in clinical use now and are a

leading HIV drug, " said Photini Sinnis, head of the Medical Parasitology

Laboratory at the NYU Langone Medical Center. " They have completely changed the

face of HIV treatment in recent years. People who take these drugs don't die of

AIDS anymore. "

Proteases are enzymes that cut proteins into their correct shapes, allowing them

to become active. HIV protease inhibitors stop the HIV virus in its tracks by

preventing one of its protease enzymes from doing that job. Without the work of

the protease, HIV proteins remain uncut and inactive, and so the HIV units,

called virions, cannot assemble them to make new virions. The body has natural

mechanisms for killing HIV virions, but it can only kill so many at a time;

preventing the virus from replicating keeps the HIV cell population to a level

that the body can handle.

Two birds, one stone

Over the past few years, several research groups (including Sinnis' group) have

noticed a surprising positive side-effect of the HIV-specific protease

inhibitors. " We're finding that the drugs have anti-malaria properties, " Sinnis

told Life's Little Mysteries, a sister site to LiveScience.

Researchers believe that HIV protease inhibitors shut down a protease present in

the malaria parasite just like they do to protease in HIV. Sinnis' group has

found that the anti-HIV drugs prevent the parasite from replicating in mice.

No human trials have been conducted, but the initial results in mice already

have HIV researchers advocating the exclusive use of protease inhibitors for HIV

treatment in Africa. " In Africa, where HIV and malaria overlap a lot, the HIV

drugs we use should be the protease inhibitors, " Sinnis said. " Then they would

have the added benefit of inhibiting malaria infection. "

At the moment, protease inhibitors are only useful for fighting malaria in

people who already have HIV. They are more toxic than many of the drugs used to

combat malaria by itself, and so wouldn't be given to a person just to treat

malaria. But if protease inhibitors can be adjusted to be less toxic, they could

be viable as stand-alone malaria medicine. And when that happens, it will be a

welcome weapon against the disease: Because malaria rapidly evolves immunity to

anti-malaria drugs, new ones are always desperately needed.

However, in order to develop a stand-alone anti-malaria drug based on the

anti-HIV drug, the specific protease in malaria that gets targeted by HIV

protease inhibitors must first be found. " If we could find the target protease,

we could design drugs that are better at targeting it, without the toxicity, "

Sinnis said.

Closing in on the target

So far, scientists have narrowed down the class of proteases that may contain

the target protease, but they have not found the specific one. Because of

malaria's complicated life cycle and unusual genome, " it's very hard to express

malaria proteins [including protease] in the lab, " Sinnis explained. This makes

experiments on malaria proteases slow-going.

But the answer may have just arrived. In a paper in the May issue of the Journal

of the Federation of American Societies for Experimental Biology (FASEB), Colin

Berry and his colleagues at Cardiff University in England report having found a

protease inhibited by HIV protease inhibitor in the Leishmania parasite, a

relative of malaria. Though the protease, called Ddi 1, hasn't been identified

in malaria, Berry's group and others believe it could very well be the target

protease everyone has been looking for.

" Our results show that Ddi1 proteins are targets of HIV [protease] inhibitors,

and indicate the Leishmania Ddi1 as the likely target for these drugs and a

potential target for antiparasitic therapy, " Berry et al. write in their paper.

" [by] identifying the protein responsible, we hope to exploit this weakness in

the parasite to develop new and effective therapeutics to combat these

devastating diseases, " they said in a press release.

" [berry et al.] are suggesting that possibly what they have found in Leishmania

may be relevant to malaria. And it's true — it might be, " Sinnis said. " The

paper certainly gives hope and ideas in terms of finding the target in the

malaria parasite. "

And when it is found, the anti-HIV wonder drug can be reworked to do wonders

against malaria as well.