RNA viruses have some of the highest mutation rates in nature. This allows them to evade the immune system to continue infecting, making it difficult to develop effective drugs. Now, a team from the Institute for Integrative Systems Biology (I2SysBio), a joint centre of the University of Valencia (UV) and the Spanish National Research Council (CSIC), has analysed, for the first time, how mutations affect the entire proteome of an RNA virus. They have found significant variability in the tolerance to mutations among different viral proteins, which will facilitate the development of drugs that reduce the likelihood of the virus developing resistance.
Based on a first comprehensive analysis of coxsackievirus B3, a human RNA virus that causes severe heart inflammation, and using a technique called deep mutational scanning, the team has determined the effect of more than 40,000 mutations and 1,300 deletions - losses of genetic material - on the virus’s viability. The results show significant variability in mutation tolerance among the different viral proteins and point to the importance of entry factors in the viral expansion process.
"We analysed the so-called pockets, which are gaps in viral proteins with properties favourable for being targeted by small drug molecules, and found twelve of these scattered across different viral proteins", explains Ron Geller, a researcher at I2SysBio and the project leader. " We then discovered that some of these pockets are highly intolerant to mutations, so it is likely that any mutation leading to drug resistance would also be lethal to the virus, preventing the spread of these mutants. Others showed very high tolerance to mutations, so they might not be good pharmacological targets", argues the CSIC researcher at this joint centre located in the University of Valencia Science Park.
Drug development
This is the first analysis of mutations affecting the complete proteome of a human RNA virus conducted to date. The results published in Plos Biology help to better understand the biology and evolution of medically relevant viruses for humans (poliovirus, rhinovirus, enterovirus A71, etc.)."One of the main challenges in developing antiviral molecules is the emergence of mutations that allow the virus to escape these drugs", explains Geller. "The data provided in this study could be used to identify regions with low tolerance to mutations, facilitating the development of drugs that reduce the probability of the virus developing resistance," he concludes.
