Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review

Abstract

Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for the cleavage of the flavivirus polyprotein, which is necessary for productive viral infection and for causing clinical infections; therefore, they are a promising drug target for devising novel drugs against different flaviviruses. This review highlights the structural details of the NS2B-NS3 proteases of different flaviviruses, and also describes potential antiviral drugs that can interfere with the viral protease activity, as determined by various studies. Moreover, optimized in vitro reaction conditions for studying the NS2B-NS3 proteases of different flaviviruses may vary and have been incorporated in this review. The increasing availability of the in silico and crystallographic/structural details of flavivirus NS2B-NS3 proteases in free and drug-bound states can pave the path for the development of promising antiflavivirus drugs to be used in clinics. However, there is a paucity of information available on using animal cells and models for studying flavivirus NS2B-NS3 proteases, as well as on the testing of the antiviral drug efficacy against NS2B-NS3 proteases. Therefore, on the basis of recent studies, an effort has also been made to propose potential cellular and animal models for the study of flavivirus NS2B-NS3 proteases for the purposes of exploring flavivirus pathogenesis and for testing the efficacy of possible drugs targets, in vitro and in vivo.

The logic of virus evolution

“…Yet another, more complicated twist in the exaptation of proteins for the function of CP is the recruitment of a chymotrypsin-like protease to replace the ancestral SJR CP in alphaviruses, a genus within Togaviridae, a family of animal positive-sense RNA viruses in the phylum Kitrinoviricota. The sequence and structure of the alphavirus CP is most similar to that of the protease from another positive-sense RNA virus family, Flaviviridae, in which this protein is not a virion component, but rather, performs a function typical of virus proteases, namely, polyprotein processing (see below) (Wahaab et al, 2021). The alphavirus CP performs a single cleavage liberating the CP from the structural polyprotein, followed by inactivation of the protease (Aggarwal et al, 2014).…”

C-Terminal Extended Hexapeptides as Potent Inhibitors of the NS2B-NS3 Protease of the ZIKA Virus

“…Subsequently, this polypeptide gets cleaved by the host and viral proteases to form three structural [Envelop (E), membrane (M), and capsid (C)] and seven non-structural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) proteins (14). Among these proteins, the NS3 encodes the serine protease, RNA helicase, RNA 5' triphosphatase (RTPase), and nucleocapsid triphosphatase (NTPase) activities (14)(15)(16)(17). The N-terminal region of NS3 in association with the membrane-bound NS2B co-factor constitutes the serine protease (14,15), which is responsible for the cleavage of the viral polyprotein and different key host proteins involved in immune response GRAPHICAL ABSTRACT | Binding of YKRKST to the protease, which fully occupies its substrate-binding site and hence may act as a potent inhibitor of the ZIKA virus protease.…”

Broad-Spectrum Antivirals and Antiviral Drug Combinations

“…In this Special Issue, authors report novel, and review known, BSAs and BCCs [8][9][10][11]. Their results indicate that the landscape of BSAs and BCCs activities and virus coverage is vast, and can be further interrogated and expanded.…”

“…Their results indicate that the landscape of BSAs and BCCs activities and virus coverage is vast, and can be further interrogated and expanded. The basic science data generated by these articles unveil new insights into the interactions between virus and host during viral infections and decipher the mechanisms of action of inhibitors and modulators of these interactions [8][9][10][11][12]. This may help us to uncover critical virus-host interactions and the underlying principles, which determine pan-and cross-family activities of BSAs, as well as understand what makes some BCCs act synergistically, something that is still largely unknown in the medical science community.…”