India has recorded its biggest outbreak of Zika virus to date (October 12th), with 32 cases confirmed in Jaipur, capital of the western state of Rajasthan.
The number of suspected cases cannot be estimated, said Veenu Gupta, the Additional Chief Secretary of the Medical and Health & Family Welfare Department for the state, adding that samples are being collected daily from all residents in a three kilometer radius. “Those who test positive are reported.”
This is India’s third outbreak since 2017.
A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.
Phylogenetic analysis reveals that contemporary epidemic strains have accumulated multiple substitutions from their Asian ancestor. Here, we show that a single serine to asparagine substitution (S139N) in the viral polyprotein substantially increased ZIKV infectivity in both human and mouse neural progenitor cells (NPCs), led to more significant microcephaly in the mouse fetus, and higher mortality in neonatal mice. Evolutionary analysis indicates that the S139N substitution arose before the 2013 outbreak in French Polynesia and has been stably maintained during subsequent spread to the Americas. This functional adaption makes ZIKV more virulent to human NPCs, thus contributing to the increased incidence of microcephaly in recent ZIKV epidemics.
Zika virus (ZIKV) is a flavivirus that has recently been associated with an increased incidence of neonatal microcephaly and other neurological disorders. The virus is primarily transmitted by mosquito bite, although other routes of infection have been implicated in some cases. The Aedes aegypti mosquito is considered to be the main vector to humans worldwide; however, there is evidence that other mosquito species, including Culex quinquefasciatus, transmit the virus. To test the potential of Cx. quinquefasciatus to transmit ZIKV, we experimentally compared the vector competence of laboratory-reared Ae. aegypti and Cx. quinquefasciatus. Interestingly, we were able to detect the presence of ZIKV in the midgut, salivary glands and saliva of artificially fed Cx. quinquefasciatus. In addition, we collected ZIKV-infected Cx. quinquefasciatus from urban areas with high microcephaly incidence in Recife, Brazil. Corroborating our experimental data from artificially fed mosquitoes, ZIKV was isolated from field-caught Cx. quinquefasciatus, and its genome was partially sequenced. Collectively, these findings indicate that there may be a wider range of ZIKV vectors than anticipated.
A Universidade Federal de Goiás (UFG) descobriu novos compostos que podem ajudar no tratamento de pessoas com o vírus da zika. Ao todo, nove substâncias foram selecionadas para testes em células infectadas, que serão feitos em uma universidade dos Estados Unidos. O objetivo é desenvolver medicamentos para combater a doença.
Em maio de 2016, a Universidade Federal de Goiás (UFG), em parceria com a World Community Grid (WCG), da International Business Machines (IBM), iniciou o projeto OpenZika, que visa identificar substâncias com potencial para tratar pessoas infectadas pelo vírus Zika. De uma lista inicial de aproximadamente 7.600 compostos, dentre eles fármacos já aprovados para uso em humanos, cinco foram selecionados e estão em fases de testes in vitro na University of California San Diego (UCSD). Agora, o grupo acaba de descobrir mais nove substâncias potenciais que serão testadas.
A descoberta surgiu em uma segunda leva de pesquisas com 260 compostos adicionais que foram testados por meio de uma triagem virtual, maior e mais diversa, contra as estruturas cristalinas da proteína helicase NS3 do vírus Zika, ligadas ao ácido ribonucleico (RNA). Os compostos também serão encaminhados para a universidade californiana ainda neste mês de março, na busca do desenvolvimento de um medicamento antiviral.
The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.
America is still suffering with the outbreak of Zika virus (ZIKV) infection. Congenital ZIKV syndrome has already caused a public health emergency of international concern. However, there are still no vaccines to prevent or drugs to treat the infection caused by ZIKV. The ZIKV NS3 helicase (NS3h) protein is a promising target for drug discovery due to its essential role in viral genome replication. NS3h unwinds the viral RNA to enable the replication of the viral genome by the NS5 protein. NS3h contains two important binding sites: the NTPase binding site and the RNA binding site. Here, we used molecular dynamics (MD) simulations to study the molecular behavior of ZIKV NS3h in the presence and absence of ssRNA and the potential implications for NS3h activity and inhibition. Although there is conformational variability and poor electron densities of the RNA binding loop in various apo flaviviruses NS3h crystallographic structures, the MD trajectories of NS3h-ssRNA demonstrated that the RNA binding loop becomes more stable when NS3h is occupied by RNA. Our results suggest that the presence of RNA generates important interactions with the RNA binding loop, and these interactions stabilize the loop sufficiently that it remains in a closed conformation. This closed conformation likely keeps the ssRNA bound to the protein for a sufficient duration to enable the unwinding/replication activities of NS3h to occur. In addition, conformational changes of this RNA binding loop can change the nature and location of the optimal ligand binding site, according to AutoLigand calculations. These are important findings to help guide the design and discovery of new inhibitors of NS3h as promising compounds to treat the ZIKV infection.