Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Abstract

Zika virus (ZIKV)—a member of the Flaviviridae family—is an important human pathogen. Its genome encodes a polyprotein that can be further processed into structural and non-structural proteins. ZIKV protease is an important target for antiviral development due to its role in cleaving the polyprotein to release functional viral proteins. The viral protease is a two-component protein complex formed by NS2B and NS3. Structural studies using different approaches demonstrate that conformational changes exist in the protease. The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design. The dynamic nature of residues binding to the enzyme cleavage site might be important for the function of the protease. Due to the charges at the protease cleavage site, it is challenging to develop small-molecule compounds acting as substrate competitors. Developing small-molecule compounds to inhibit protease activity through an allosteric mechanism is a feasible strategy because conformational changes are observed in the protease. Herein, structures and dynamics of ZIKV protease are summarized. The conformational changes of ZIKV protease and other proteases in the same family are discussed. The progress in developing allosteric inhibitors is also described. Understanding the structures and dynamics of the proteases are important for designing potent inhibitors.

Investigating the Antiviral Therapeutic Potentialities of Marine Polycyclic Lamellarin Pyrrole Alkaloids as Promising Inhibitors for SARS-CoV-2 and Zika Main Proteases (Mpro)

“…NS1 is involved in viral replication, infection, and interacts with the host immune factors when secreted extracellularly for immune evasion and pathogenesis [41]. NS3 consists of a protease domain that linked to NS2B to form a protease complex [15,40,42]. NS5 contains RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) domains essential for viral replication, translation, and evasion of host immune response [43].…”

“…The Zika virus protease is a serine protease with a catalytic triad formed by three residues, His51, Asp75, and Ser135, in its active site in the N-terminal region of NS3 and required a small hydrophilic proportion of NS2B as cofactor domain [44]. The protease of ZIKV is responsible for cleaving four joints between non-structural proteins (NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5) and two sites within the C protein (C/Ci) and NS4A (NS4A/2K), which are essential to release functionally structural and non-structural proteins [15,44,45]. Hence, inhibiting the protease activity of the Zika virus represents an important strategy in the fight against this virus.…”

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

“…(18). Therefore, it is necessary to design substrate competitive inhibitors to inhibit the protease activities of NS2B-NS3 protease to contain the ZIKV (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…Several attempts were made to design substrate competitive inhibitors to occupy the substrate-binding site of the NS2B-NS3 protease of the ZIKV. These inhibitors include (1) small molecules (19)(20)(21)(22)(23)(24)(25)(26)(27), ( 2) peptidomimetics (28)(29)(30)(31)(32)(33), and (3) peptide inhibitors (34,35). As the protease active site is surrounded by negatively charged amino acids (acidic residues), the binding of small molecule neutral inhibitors was not effective.…”

“…Although the bindings of different inhibitors to the unprimed sites (S1-S4) are well studied (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), the inhibitor binding to the prime sites (S1' and S2') is rarely studied. Therefore, it is also desirable to understand the effects of prime site residues on the stability of peptide-protease complexes.…”