Researchers said Wednesday they had discovered four natural mosquito repellents to succeed DEET, a compound whose origins go back to World War II.
DEET -- the abbreviation for N,N-diethyl-meta-toluamide -- was introduced by the US Army in 1946 after troops deployed in the Pacific theatre fell sick from malaria and other mosquito-borne diseases.
It remains the primary insect repellent in use today, but has many limitations.
It has to be applied frequently and is expensive, which rules it out for combatting disease in regions where malaria is endemic.
It also dissolves types of plastic, synthetic fabrics and painted surfaces.
More worryingly, there is some evidence that flies and mosquitoes are developing resistance to it, and that the chemical disrupts an important enzyme in the mammalian nervous system called acetylcholinesterase.
In experiments that combined entomology and data-crunching computing, scientists at the University of California at Riverside uncovered four alternatives that may send DEET into retirement after 67 years.
"The candidates contain chemicals that do not dissolve plastic, are affordable and smell mildly like grapes, with three considered safe in human foods," says their study published Wednesday in the journal Nature.
"Our findings pave the way to discover new generations of repellents that will help fight deadly insect-borne diseases worldwide."
The scientists' first step was to understand how mosquitoes sense DEET and become repelled by it.
For this, they turned to a cousin of the mosquito called the fruit fly, or Drosophila melanogaster, one of the most closely-studied lab creatures of all.
The answer, they found, lies in a receptor called Ir40a, found in nerve-system cells in a pit-like structure in the fruit fly's antenna.
The next step was to look for an odour molecule that would fit and activate the receptor, rather like a key turns a lock.
It also had to be a natural substance, found in fruits, plants or animals.
The data pool proved to be a mini-ocean, comprising nearly half a million potential compounds.
This was whittled down to nearly 200. Of these, 10 compounds seemed the most promising and were put to the test on fruit flies.
Of the 10, eight turned out to be good repellents on fruit flies. Four of them were then tested on mosquitoes, all of which worked.
The good news is that out of the four, three have already been approved as food flavours or fragrances by the US Food and Drug Administration (FDA).
Called methyl N,N-dimethyl anthranilate, ethyl anthranilate and butyl anthranilate, they can be applied to bed nets, clothes and curtains to ward off insects, say the scientists.
The secret behind the breakthrough was to locate the Ir40a receptor and develop an algorithm to screen potential chemicals, said Anandasankar Ray, an associate professor of entomology.
Ir40a, according to the probe, is highly conserved, a scientific term meaning that it shows little signs of evolutionary change.
That, too, is good news. One of the problems for drug designers is when they face a moving target -- a mutational shift in DNA that means the treatment becomes less effective.
The receptor is also common across many flies and other insects that are a pest for humans and plants.
"Our findings could lead to a new generation of cheap, affordable repellents that could protect humans, animals and, in the future, our crops," said Ray.