Zika virus proteins at an atomic scale: how does structural biology help us to understand and develop vaccines and drugs against Zika virus infection?

Abstract

In Brazil and in other tropical areas Zika virus infection was directly associated with clinical complications as microcephaly in newborn children whose mothers were infected during pregnancy and the Guillain-Barré syndrome in adults. Recently, research has been focused on developing new vaccines and drug candidates against Zika virus infection since none of those are available. In order to contribute to vaccine and drug development efforts, it becomes important the understanding of the molecular basis of the Zika virus recognition, infection and blockade. To this purpose, it is essential the structural determination of the Zika virus proteins. The genome sequencing of the Zika virus identified ten proteins, being three structural (protein E, protein C and protein prM) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5). Together, these proteins are the main targets for drugs and antibody recognition. Here we examine new discoveries on high-resolution structural biology of Zika virus, observing the interactions and functions of its proteins identified via state-of-art structural methodologies as X-ray crystallography, nuclear magnetic resonance spectroscopy and cryogenic electronic microscopy. The aim of the present study is to contribute to the understanding of the structural basis of Zika virus infection at an atomic level and to point out similarities and differences to others flaviviruses.

Protective Effects of Caffeine on Chikungunya and Zika Virus Infections: An in Vitro and in Silico Study

“…It has also been shown that several other ligands associated with the RdRp proteins have at least one adenosyl group, [69] which is similar to the chemical structure of caffeine; therefore, it could be speculated that caffeine acts by inhibiting these particular proteins, leaving the virus without replicative capacity after entering the host cell. Another study showed that caffeine inhibits RNA-dependent DNA polymerase (RdDp) activity of the Rauscher leukemia virus when endogenous viral RNA and poly(rA) • (dT) 12-18 or purified RdDP from avian myeloblastosis virus were used as templates.…”

Protective Effects of Caffeine on Chikungunya and Zika Virus Infections: An in Vitro and in Silico Study

“…It has also been shown that several other ligands associated with the RdRp proteins have at least one adenosyl group, [69] which is similar to the chemical structure of caffeine; therefore, it could be speculated that caffeine acts by inhibiting these particular proteins, leaving the virus without replicative capacity after entering the host cell. Another study showed that caffeine inhibits RNA-dependent DNA polymerase (RdDp) activity of the Rauscher leukemia virus when endogenous viral RNA and poly(rA) • (dT) 12-18 or purified RdDP from avian myeloblastosis virus were used as templates.…”

Identification of Zika Virus NS1-Derived Peptides with Potential Applications in Serological Tests

“…When analyzing the three-dimensional structure of ZIKV NS1, the six epitopes were arranged in the C terminal B ladder region (specifically in positions between 248–352) and showed pronounced exposure on the protein surface [ 42 , 55 , 56 ]. These data agree with the truncated ZIKV-NS1 (corresponding to the C terminal region) previously described and used to generate these antibodies [ 26 , 47 ].…”

Unravelling the epidemiological diversity of Zika virus by analyzing key protein variations

“…The modeling analysis indicate that the presence of an Alanine in the position 988 would destabilize NS1 protein regarding to a Valine in the same position. This change is located in the beta ladder domain, which is responsible for NS1 oligomerization 49 . Since NS1 functions highly depend on its symmetric oligomerizations, changes in this domain could directly impact in the protein functionality.…”

“…The last two analyzed variations correspond to different domains of the E protein. On one hand, the variant I459V localizes in the Domain I, which plays crucial roles in essential conformational changes of E protein during the ZIKV infection process 49 . The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position.…”

“…The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position. On the other hand, the variant M763V is positioned in the Domain III, which is mainly recognized as the primary viral receptor binding region 49 . In this case, the presence of a Valine in the position 763, which was predicted as a destabilizing change with regard to a Methionine in the same position, was detected in every African and Asian Pre Epidemic analyzed sequence.…”

Protective Effects of Caffeine on Chikungunya and Zika Virus Infections: An in Vitro and in Silico Study

“…It has also been shown that several other ligands associated with the RdRp proteins have at least one adenosyl group, [69] which is similar to the chemical structure of caffeine; therefore, it could be speculated that caffeine acts by inhibiting these particular proteins, leaving the virus without replicative capacity after entering the host cell. Another study showed that caffeine inhibits RNA-dependent DNA polymerase (RdDp) activity of the Rauscher leukemia virus when endogenous viral RNA and poly(rA) • (dT) 12-18 or purified RdDP from avian myeloblastosis virus were used as templates.…”

Identification of Zika Virus NS1-Derived Peptides with Potential Applications in Serological Tests

“…When analyzing the three-dimensional structure of ZIKV NS1, the six epitopes were arranged in the C terminal B ladder region (specifically in positions between 248–352) and showed pronounced exposure on the protein surface [ 42 , 55 , 56 ]. These data agree with the truncated ZIKV-NS1 (corresponding to the C terminal region) previously described and used to generate these antibodies [ 26 , 47 ].…”

Unravelling the epidemiological diversity of Zika virus by analyzing key protein variations

“…The modeling analysis indicate that the presence of an Alanine in the position 988 would destabilize NS1 protein regarding to a Valine in the same position. This change is located in the beta ladder domain, which is responsible for NS1 oligomerization 49 . Since NS1 functions highly depend on its symmetric oligomerizations, changes in this domain could directly impact in the protein functionality.…”

“…The last two analyzed variations correspond to different domains of the E protein. On one hand, the variant I459V localizes in the Domain I, which plays crucial roles in essential conformational changes of E protein during the ZIKV infection process 49 . The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position.…”

“…The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position. On the other hand, the variant M763V is positioned in the Domain III, which is mainly recognized as the primary viral receptor binding region 49 . In this case, the presence of a Valine in the position 763, which was predicted as a destabilizing change with regard to a Methionine in the same position, was detected in every African and Asian Pre Epidemic analyzed sequence.…”

Protective Effects of Caffeine on Chikungunya and Zika Virus Infections: An in Vitro and in Silico Study

“…It has also been shown that several other ligands associated with the RdRp proteins have at least one adenosyl group, [69] which is similar to the chemical structure of caffeine; therefore, it could be speculated that caffeine acts by inhibiting these particular proteins, leaving the virus without replicative capacity after entering the host cell. Another study showed that caffeine inhibits RNA-dependent DNA polymerase (RdDp) activity of the Rauscher leukemia virus when endogenous viral RNA and poly(rA) • (dT) 12-18 or purified RdDP from avian myeloblastosis virus were used as templates.…”

Identification of Zika Virus NS1-Derived Peptides with Potential Applications in Serological Tests

“…When analyzing the three-dimensional structure of ZIKV NS1, the six epitopes were arranged in the C terminal B ladder region (specifically in positions between 248–352) and showed pronounced exposure on the protein surface [ 42 , 55 , 56 ]. These data agree with the truncated ZIKV-NS1 (corresponding to the C terminal region) previously described and used to generate these antibodies [ 26 , 47 ].…”

Unravelling the epidemiological diversity of Zika virus by analyzing key protein variations

“…The modeling analysis indicate that the presence of an Alanine in the position 988 would destabilize NS1 protein regarding to a Valine in the same position. This change is located in the beta ladder domain, which is responsible for NS1 oligomerization 49 . Since NS1 functions highly depend on its symmetric oligomerizations, changes in this domain could directly impact in the protein functionality.…”

“…The last two analyzed variations correspond to different domains of the E protein. On one hand, the variant I459V localizes in the Domain I, which plays crucial roles in essential conformational changes of E protein during the ZIKV infection process 49 . The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position.…”

“…The presence of a Valine in position 459, which was restrictive and representative of the African group, implies a destabilizing change with respect to an Isoleucine in the same position. On the other hand, the variant M763V is positioned in the Domain III, which is mainly recognized as the primary viral receptor binding region 49 . In this case, the presence of a Valine in the position 763, which was predicted as a destabilizing change with regard to a Methionine in the same position, was detected in every African and Asian Pre Epidemic analyzed sequence.…”