Dengue virus serotype 2 NS2B-NS3 protease (DENV2 NS2B-NS3pro) (DENV2 NS2B-NS3pro)

The Dengue virus serotype 2 (DENV2) NS2B-NS3 protease is a heterodimeric enzyme complex essential for the replication and assembly of the dengue virus. It is composed of the N-terminal serine protease domain of the non-structural protein 3 (NS3) and a 40-residue hydrophilic region of the NS2B protein, which serves as a necessary cofactor for catalytic activity and proper folding (UniProt: P03314). The primary biological function of this protease is the proteolytic processing of the viral polyprotein at several junctions, including NS2A/NS2B, NS2B/NS3, NS3/NS4A, and NS4B/NS5, to release individual functional proteins (PubMed: 27507198). Additionally, the protease plays a role in subverting the host's immune system by cleaving human STING (stimulator of interferon genes), thereby inhibiting the type I interferon response (PubMed: 22310282). As a central component of the viral life cycle, it is considered a high-priority therapeutic target for the treatment of Dengue fever and its more severe forms, such as Dengue Hemorrhagic Fever (DHF). While no drugs targeting this protease are currently FDA-approved, research is focused on developing competitive inhibitors that target the active site or allosteric inhibitors that disrupt the NS2B-NS3 interaction (PubMed: 31433177). The enzyme's active site contains a classic catalytic triad consisting of His51, Asp75, and Ser135, which is a common focus for structure-based drug design. Challenges in drug development include achieving high selectivity over human serine proteases and overcoming the high mutation rate of the virus. Successful inhibition of this protease would effectively halt viral replication and reduce the severity of the infection.

Other names

DENV2 NS2B-NS3 serine proteaseNS3 proteaseDengue virus type 2 NS3 protease complexNS2B-NS3pro

Inhibition of the NS3 serine protease activity by binding to the catalytic triad (His51, Asp75, Ser135) or the substrate-binding pocket, preventing viral polyprotein cleavage (PubMed: 31433177).