Since it was first identified in the Zika forest of Uganda, Africa, the Zika virus has spread across Asia, the Pacific and more recently the Americas. Serious concerns about the virus have been raised since 2015, due to a rapid rise in infections in the Americas coinciding with an increase in cases of microcephaly and other neurological disorders.
A link between Zika virus in expectant women and microcephaly in fetuses and newborns was confirmed by the Centers for Disease Control in April 2016. Microcephaly is a condition in which a child’s brain fails to develop properly in the womb, often leading to diminished brain size, impaired cognitive ability, motor control problems, seizures and related symptoms.
Other neurological conditions suspected of being associated with Zika include:
- Guillain-Barré syndrome, which causes sudden muscle weakness and even paralysis in adults.
- Myelitis, which is an infection of the spinal cord.
- Meningoencephalitis, an inflammation of the brain and surrounding tissues, usually caused by infection.
These neurological effects have caused great concern and prompted the World Health Organization to form a Zika Emergency Committee to address the problem.
What is Zika?
The Zika virus is a member of the flavivirus genus, which includes dengue, yellow fever, West Nile viruses and others – viruses which are mostly transmitted to humans by a mosquito or tick bite. The Zika virus is transmitted primarily by two kinds of mosquitos: the yellow fever mosquito (Aedes aegypti) and the Asian tiger mosquito (Aedes albopictus). Sexual transmission of the Zika virus has also been recently confirmed, as well as transmission via the blood. Urine and saliva have been found to contain the virus, too.
The symptoms of a Zika infection are usually mild, consisting of fever, rash, joint pains, conjunctivitis (red eyes), headache and/or swollen lymph nodes. However, the link between Zika virus in pregnant women and microcephaly in fetuses and newborns has prompted several countries to recommend delaying pregnancy in affected areas until more is understood. More effective solutions are needed to combat the Zika epidemic.
Even though the virus was first identified in 1947, little research has been done until the recent outbreak in the Americas. The latest version of the Zika virus genome was sequenced in 2016, and scientists are using that genetic information to work toward determining the proteins involved in the disease and what their structures are, which could help in the development of a vaccine or antiviral medicines.
Although there are also efforts to eradicate the Aedes mosquitoes that spread Zika, the disease is likely to continue to spread rapidly in the Americas, because the general human population in this region has not been exposed to the virus previously and therefore has little immunity to it. In addition, the Aedes aegypti mosquito is more difficult to eradicate than other types of mosquitoes, because it tends to hide inside homes, which makes widespread insecticide spraying strategies less effective. Many mosquitoes have also become increasingly resistant to the insecticides that are used to try to kill them.
There is currently no vaccine to prevent infection with the Zika virus, nor is there any known antiviral drug to treat patients who have contracted the virus. Scientists do not yet have computational research methods that could take advantage of World Community Grid to develop a vaccine. But World Community Grid’s vast computational resources can instead play a role in helping researchers discover and develop antiviral drugs to combat Zika.
The Proposed Solution
Developing Drug Treatments to Combat Zika
The OpenZika project aims to help scientists develop antiviral drugs to fight Zika. Antiviral drugs help stop a disease once a person is already infected, when it is usually too late for a vaccine. Some antiviral drugs can also be used “prophylactically,” to prevent the infection from occurring or to prevent an infected person from spreading it to others. However, this prevention only lasts while taking the antiviral drug—it is not a vaccine.
To develop these drugs, scientists need to evaluate millions of chemical compounds to determine which might be effective at disabling the proteins a virus needs to reproduce or to infect cells. This often begins with determining the “crystal structure,” at the atomic scale, of these key proteins, then screening chemical compounds to see which can attach, or “dock”, to the protein and potentially disable it. To conduct such a screening process in a “wet laboratory” is very expensive and time consuming. That is where World Community Grid can help—by allowing researchers to use virtual screening techniques to systematically evaluate millions of compounds against many different Zika proteins. The researchers can then predict which compounds are more likely to be effective in subsequent wet lab tests that measure Zika virus replication or the ability of the virus to infect cells.
To perform such computational experiments, OpenZika researchers are using a proven virtual screening tool called AutoDock VINA, developed by the Olson laboratory at The Scripps Research Institute, which has also partnered with World Community Grid on two other projects: FightAIDS@Home and GO Fight Against Malaria. Several other World Community Grid projects have also used VINA, including Outsmart Ebola Together, Drug Search for Leishmaniasis and Say No to Schistosoma.
The exact, atomic scale structures of most of the proteins that play a key role in the Zika virus lifecycle have yet to be determined (by experiments called “X-ray crystallography”). Until then, scientists will use approximate structures derived from a process called “homology modeling.” This involves using the genetic information for the Zika proteins and looking for very similar target proteins from other organisms, such as the dengue virus, for which some of the protein structures are known at atomic detail. These known structures (called “templates”) are then used as the basis to develop models of the targets that likely resemble the Zika proteins. In previous studies, homology models have been successfully used to identify new compounds that were proven to be effective against pathogenic protein targets. World Community Grid projects such as Genome Comparison and Uncovering Genome Mysteries have been helpful in identifying similar proteins.
AutoDock VINA will be used to screen millions of chemical compounds against these target proteins to identify promising candidates for early laboratory testing. As additional and more accurate Zika-related protein structures are determined, such structures will also be used as targets for screens on OpenZika. This way, we hope to get a head start on the long process of discovering and developing antiviral drugs against Zika. We will also perform these screens against the crystal structures of the templates from other flaviviruses to see if we can discover broad-spectrum antiviral drugs that can help fight multiple types of flaviviruses.
The specific goals of the project are:
- Screen compounds from the ZINC database, a collection of millions of compounds for virtual screening, against Zika protein homology models.
- Screen millions of compounds against experimentally determined Zika protein structures, as soon as these are known.
These screening results will all be made publicly available, opening the door for other scientists to also use this data to help develop Zika treatments.
- http://bdz.sbu.unicamp.br/wp/ (in Portuguese)