Abstract
Alphaviruses are enveloped, positive single-stranded RNA viruses, typically transmitted by arthropods. They often cause arthralgia or encephalitic diseases in infected humans and there is currently no targeted antiviral treatment available. The re-emergence of alphaviruses in Asia, Europe, and the Americas over the last decade, including chikungunya and o’nyong’nyong viruses, have intensified the search for selective inhibitors. In this review, we highlight key molecular determinants within the alphavirus replication complex that have been identified as viral targets, focusing on their structure and functionality in viral dissemination. We also summarize recent structural data of these viral targets and discuss how these could serve as templates to facilitate structure-based drug design and development of small molecule inhibitors.
Highlights
Alphaviruses belong to the Togaviridae family [1]
Old World alphaviruses such as chikungunya virus (CHIKV), o’nyong’nyong virus (ONNV), and sindbis virus (SINV) are arthritogenic and commonly cause febrile illness accompanied by rash, polyarthralgia and chronic arthritis [4,5,6,7,8]
Deletion and mutation studies of the RNA-dependent RNA polymerase (RdRp) domain of SINV Non-Structural Protein 4 (nsP4) demonstrated terminal adenylyltransferase (TATase) activity, suggesting it has a potential role in maintenance of the 30 poly-A tail at the 30 -end of positive-sense RNAs [66]
Summary
Alphaviruses belong to the Togaviridae family [1]. They are arboviruses that are transmitted to humans through the mosquito species Aedes aegypti and Aedes albopictus, where they cause various diseases and can be broadly divided into arthritogenic [2] and encephalitogenic [3]. Translation of the viral RNA by host cell translational translational machinery produces two non-structural protein (nsP). P1234 is expressed as as a read-through of an non-structural protein (nsP) precursors (P123 or P1234). The translation of 26S subgenomic positive sense RNA generates a single structural polyprotein, which is cleaved into five structural proteins: the Capsid (C), two major envelope glycoproteins E1 which is cleaved into five structural proteins: the Capsid (C), two major envelope glycoproteins and E2, and two small cleavage products (E3, 6K) (Figure 1A). The organization of alphavirus RC focusing on the function and structure of nsP2 protease will be illustrated These proteins play important roles in the various replication stages of the viral genome. Old World alphaviruses, as determined by the recently solved structures of VEEV, SINV and CHIKV nsP2 proteases, makes it an ideal target for designing specific and pan-alphavirus protease inhibitors [29,30,31,32]
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