The RNA helicase/NTPase domain in the C-terminal plays a critical role in RNA synthesis and replication of the viral genome.
It contains an N-terminal protease domain and a C-terminal RNA helicase/NTPase domain. The flavivirus NS3 protein is one of the most important nonstructural proteins because of its multiple enzymatic activities. Its seven nonstructural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5) are critical for virus replication, virion assembly, and host invasion. ILHV is a single-stranded and positive-sense RNA virus. Therefore, in-depth studies are thus warranted on the proteins of these dangerous pathogens. As a result, their potential danger to human health cannot be ignored. Notably, arboviruses have the potential to invade the CNS, resulting in long-term neurological sequelae. Thus, although the current number of ILHV infection caused is low, an increasing number of arbovirus infected patients show unusual clinical manifestations. This ties to encephalitic diagnoses that can lead to fatal outcomes. ILHV’s impact upon the central nervous system (CNS) involvement has also been reported in a handful of documented human cases. Symptoms of ILHV infection include fever, headache, myalgia, arthralgia, and photophobia. ILHV has been transmitted over a wide geographic range encompassing the Caribbean, Central America, and South America particularly in Brazil and Trinidad. It was discovered in Aedes and Psorophora spp. ILHV was first identified in the northeast of Brazil in 1994 near the Ilheus City. These Brazilian flavivirus strains, all found to cause sporadic cases of human infection, specifically include Cacicapore virus (CPCV), Bussuquara virus (BUSV), Rocio virus (ROCV), Saint Louis encephalitis virus (SLEV), and Ilheus virus (ILHV). Certain strains of public health threatening flaviviruses have been isolated in Brazil. Dengue virus (DENV), Yellow fever virus (YFV), and Zika virus (ZIKV) belong to the flavivirus, which have been responsible for massive outbreaks and attracted public attention. Many flaviviruses caused significant infections and diseases in humans among the emerging diseases. High-resolution ILHV helicase structural analysis demonstrates the key amino acids of ATPase activities and could be useful for the design of inhibitors targeting the helicase of ILHV. Moreover, we docked two small molecule inhibitors of DENV helicase (ST-610 and suramin) to the ILHV helicase and found that these two molecules had the potential to inhibit the activity of ILHV helicase as well. Our structure-guided mutagenesis revealed that R26A, E110A, and Q280A greatly reduced the ATPase activities. This was found to be relatively lower than that of the DENV, ZIKV, MVE, and ALSV helicases. ILHV helicase enzymatic activity was also characterized. However, the P-loop in the active site showed a distinctive conformation reflecting a different local structural rearrangement. This suggested that ILHV helicase adopts an identical mode in recognizing ATP/Mn 2+. Comparisons with related flavivirus helicases indicated that both the NTP and the RNA-ILHV helicase binding sites were conserved across intra-genus species. We then conducted molecular docking of ATP-Mn 2+ to the ILHV helicase.
We determined the crystal structure of the ILHV helicase at 1.75-Å resolution. Thus, ILHV helicase is an ideal target for inhibitor design. This allows it to perform ATP hydrolysis to generate energy as well as sustain double-stranded RNA’s unwinding during ILHV genome replication. The ILHV helicase, like other flavivirus helicases, possesses 5ʹ-triphosphatase activity. No specific vaccines or drugs are currently available for the treatment of ILHV infections.
It was first identified in Ilheus City in the northeast Brazil before spreading to a wider geographic range.
The Ilheus virus (ILHV) is an encephalitis associated arthropod-borne flavivirus.
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