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Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold.

ABSTRACT: Alphaviruses such as Ross River virus (RRV), chikungunya virus (CHIKV), Sindbis virus (SINV), and Venezuelan equine encephalitis virus (VEEV) are mosquito-borne pathogens that can cause arthritis or encephalitis diseases. Nonstructural protein 4 (nsP4) of alphaviruses possesses RNA-dependent RNA polymerase (RdRp) activity essential for viral RNA replication. No 3D structure has been available for nsP4 of any alphaviruses despite its importance for understanding alphaviral RNA replication and for the design of antiviral drugs. Here, we report crystal structures of the RdRp domain of nsP4 from both RRV and SINV determined at resolutions of 2.6 Å and 1.9 Å. The structure of the alphavirus RdRp domain appears most closely related to RdRps from pestiviruses, noroviruses, and picornaviruses. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) and nuclear magnetic resonance (NMR) methods showed that in solution, nsP4 is highly dynamic with an intrinsically disordered N-terminal domain. Both full-length nsP4 and the RdRp domain were capable to catalyze RNA polymerization. Structure-guided mutagenesis using a trans-replicase system identified nsP4 regions critical for viral RNA replication.

SUBMITTER: Tan YB

PROVIDER: S-EPMC8789068 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alphaviruses, such as Chikungunya virus, O’Nyong–Nyong virus, Ross River virus, have been widely known to cause fever, rash, and rheumatic diseases. In addition, several other alphaviruses, for instance Eastern equine encephalitis virus, Venezuelan equine encephalitis virus, and Western equine encephalitis virus, potentially cause fatal encephalitis in humans. These diseases are considered as neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The replication process in alphaviruses depends on four nonstructural proteins, NSP1–NSP4, which are produced as a single polyprotein. Therefore, the Alphavirus-mediated diseases in humans remain challenging among the virologists worldwide. Thus researchers are trying to find out proficient approaches, including the discovery of novel chemotherapeutic agents for the possible management and treatment of infected patients. Attempts were also made to identify an active compound against alphaviruses from natural sources. The genomes of various alphaviruses have already been revealed, and the function of proteins may be predicted by homology modeling, with the known proteins of closely related viruses. With the help of this information of protein modeling and subsequent virtual screening approach, the research teams will be able to identify few potential leads. The drug discovery against various alphaviruses is still in its early stages. Moreover, consolidating the available information and making it available for the scientific community are urgent requirements to expedite the research of potential drug discovery. The current chapter describes the techniques available to prevent Alphavirus infection and to treat Alphavirus-associated malignancies. In addition, we also discuss the recent outcomes in the fields of synthetic and natural medicinal chemistry research that were solely aimed to fight against Alphavirus infection. Thus the present chapter may also help and expedite the drug discovery and development of inhibitors against nonstructural proteins of various alphaviruses.

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Crystal structures of alphavirus nonstructural protein 4 (nsP4) reveal an intrinsically dynamic RNA-dependent RNA polymerase fold.

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