Research groups from around the world have identified potential therapeutic targets for treating active Zika virus.
Just as federally supported efforts to develop a vaccine to prevent future Zika virus infections have gained momentum, thanks in large part to increased funding, now multiple research groups are also active in identifying potential therapeutic targets for treating active disease.
Indeed, a team of scientists from various institutions in Poland has demonstrated a unique role for the serine protease NS3, which is active in flaviviruses such as the Zika virus, and is responsible for protein processing and replication. Their work, which was published online on October 7 by the journal FEBS Letters, highlights that NS3 is expressed by Zika virus and, according to the authors, “pave[s the] way for screening potential intracellular substrates of NS3 and for developing specific inhibitors of this [Zika virus] protease.”
Meanwhile, a team of researchers in Rome has developed a model demonstrating how the Zika virus evolves as it interacts with the human immune system and spreads among populations, using homology modelling and T- and B-cells epitope prediction. Their findings were published on September 27 in the journal Pathogens and Global Health.
With regard to NS3, earlier research has established that sequence identity between flaviviruses such as Zika virus and West Nile and protease domains is high. In fact, flavivirus NS3 protease is already a clinically proven target for antiviral therapy in hepatitis C, the Polish authors note.
To explore its potential role in the Zika virus, the authors sought to profile the P1-P4 substrate specificity of the NS2B-NS3 protease via combinatorial chemistry, using the “split-and-mix” method to link a C-terminal fragment of the NS2B cofactor domain to the N-terminus of NS3 protease via 9 amino acid linker G4SG4. They found that Zika virus NS3 protease “follows the typical pattern for flaviviruses” in that it processes the P1 arginine at the C-terminal end. In West Nile virus, earlier studies have suggested that a Lys-Lys combination is preferred at the P3-P2 sites, whereas yellow fever viruses and Dengue proteases prefer P2 arginine and P3 lysine. Conversely, the Polish researchers highlighted that, in the Zika virus, the optimal P3-P2 combination appears to be Lys-Lys or Lys-Arg, as the Zika NS3 protease has a “very strong requirement for lysine.”
The authors did not respond to requests for comment; however, they wrote in their study, “Our results demonstrate that this enzyme shares substrate specificities previously described for other flaviviruses, with some peculiarities. Precise mapping of the substrate specificity will allow for the development of highly specific inhibitors with minimal effect on cellular proteases.
Additionally, this data will enable further studies of potential cellular targets of the [Zika virus] NS3 protease… Our findings will allow for the future screening of potential cellular substrates and facilitate better understanding of the [Zika virus] infectious process. These results will also allow for the design of novel protease inhibitors with high specificity towards the [Zika virus] protease.”
In another genome analysis, their Italian counterparts found that the Zika virus has two distinct genotypes—African and Asiatic—as well as two separate clades, with Clade I representing African gene sequences and Clade II characterizing Asiatic and Brazilian sequences.
Interestingly, given that Brazil has been the epicenter of the current Zika virus outbreak since 2014, they noted that the Brazilian sequence appears to be closely related to a sequence from French Polynesia, suggesting that the mosquito-borne virus may have been introduced to the South American country during the Va'a World Sprint Canoeing Championships, which were held in Rio de Janeiro that same year. The competition included a team from French Polynesia.
They also demonstrated that antigenic variability, and as well as pre-existing immunity caused by cross-reactions with other viruses such as Dengue and Chikungunya, may influence Zika virus infection. Of course, these cross-reactions have also served to make diagnosis of Zika virus infection a clinical challenge, which may have been a factor in its continued spread.
The authors of the Pathogens and Global Health paper could not be reached for comment; however, they noted that “understanding the differences and similarities between Zika and other flaviviruses, such as the Dengue fever and Chikungunya viruses, is essential if effective drugs, vaccines and Zika-specific immunological tests for large population screening are to be designed.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.