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.