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.

Zika Virus Pathogenesis: A Battle for Immune Evasion

“…Moreover, determining the molecular interplay between the ZIKV genome and viral proteins with the IFN and T cell responses and antiviral signals is also crucial to improving vaccine strategies based on mutant live-attenuated viral candidates that need to induce adaptive cellular and humoral immune protective responses, also helping type-I IFN antiviral responses [ 128 , 129 , 169 , 382 ].…”

“…The positive-sense single-stranded RNA (+ssRNA) genome of ZIKV is approximately 11 Kb in size and codes one large polyprotein that is processed by viral and host proteases into three structural (C, prM/M, and E) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) [ 73 , 168 , 169 ] ( Figure 1 ), as reported for other flaviviruses [ 170 , 171 ]. In infected cells, all these proteins are produced following genome replication and translation in the cytoplasm, where the structural proteins together with some NS proteins drive virion assembly at endoplasmic reticulum (ER) membranes and subsequent egress or new viral particles [ 172 ].…”

Differential expression of miRNAs in a human developing neuronal cell line chronically infected with Zika virus

“…Capsid dimers can bind a wide range of nucleic acid templates including the host RNAs, interfering in RNA splicing and RNA transcription. Capsid also enter the nucleolus and interacts with miRNAs and, therefore, may quell the molecular immune response against ZIKV [20,22]. Capsid protein expresses hydrophobic and hydrophilic regions that appear to play important roles in the pathogenesis of the virus.…”

“…Capsid protein expresses hydrophobic and hydrophilic regions that appear to play important roles in the pathogenesis of the virus. Capsid also causes significant dysregulation of host ribosomal biogenesis [20,[22][23][24][25]. The hydrophobic regions of capsid proteins interact with the membrane of the endoplasmic reticulum (ER) whereas the hydrophilic region interacts with viral RNA.…”

A Review on the Current Knowledge on ZIKV Infection and the Interest of Organoids and Nanotechnology on Development of Effective Therapies against Zika Infection

“…The viral genome is associated and protected by the icosahedral capsid, which is further surrounded by a glycoprotein envelope composed by over a hundred protein E and M molecules [9]. Protein E is considered to be the most important, as it is the most abundant in the virus surface and has a big relevance in the search for vaccines or neutralizing antibodies against ZIKV infection [8,10,11]. The infectivity ability of ZIKV mostly relies upon prM, E, NS1, NS3 and NS5 proteins and, while some of these proteins are very similar across different members of the Flavivirus Genus, prM, E and NS3 in ZIKV are significantly different to those present in other members of the genus, consequently and possibly explaining the differences in the transmission routes, cellular tropism, tissue persistence and other biological traits [10,12].…”