Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor

Abstract

Zooming in on the Zika virus protease The lack of a vaccine or antiviral drugs to combat the Zika virus has scientists scrambling to identify and better characterize potential drug targets. One attractive candidate is the NS2B/NS3 viral protease, which, together with host cell proteases, cleaves the viral polyprotein into the individual proteins required for viral replication. Lei et al. report the crystal structure of this protease bound to a peptido-mimetic inhibitor. The structure reveals key interactions that probably contribute to the high catalytic efficiency of this enzyme relative to other flaviviruses, indicating promising starting points for drug design. Science , this issue p. 503

Mechanisms of activation and inhibition of Zika virus NS2B-NS3 protease

“…NS2B-NS3pro can be activated readily by adding a widely used synthetic substrate AC-LKKR-AMC [10]. Using Michaelis-Menten kinetics we determined that the K m and k cat are 85.3 ± 2.1 μM and 1.149 ± 0.069 s -1 , respectively (Supplementary information, Figure S1D), which are comparable to the dengue virus (DENV) and the West Nile virus (WNV) NS2B-NS3pros [11,12], but different from ZIKV NS2B-NS3 (R95A/ R29G), which has an increased activity [8]. To discover potential inhibitors of ZIKV, we screened small molecule compounds against ZIKV NS2B-NS3pro.…”

“…Flavivirus NS3pro exists predominantly in an inactive state; however, upon association with the NS2B viral protein, its enzymatic activity increases by 3 300-6 600-fold [7]. The recent structure of ZIKV NS2B-NS3pro in complex with a boronate inhibitor has provided some important insights for drug design [8]. However, it remains still largely unknown the exact molecular mechanism of ZIKV NS3pro activation by NS2B, which requires a structure of the apo NS2B-NS3pro complex.…”

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

“…The NS2B-bound crystal structures of the Dengue NS3 protease (PDB ID: 3U1I [43]) and of the Zika NS3 protease (PDB ID: 5LC0 [44]) were used as docking targets to predict the possible bound conformations of these compounds. The program Autodock Vina [47] was used to dock the molecules into two putative binding sites corresponding to two NS2B residues that bind to NS3: L51/M51 and V53/I53.…”

“…To explore the drugs' potential modes of actions, we docked temoporfin, niclosamide, and nitazoxanide to the crystal structure of the ligand-bound NS3 proteases of DENV3 (PDB ID: 3U1I) [43] and ZIKV (PDB ID: 5LC0) [44] after removing the NS2B peptides. We first employed a SiteMap [45] calculation on NS3pro of DENV3 to identify potential pockets on NS3 for binding of these drugs.…”

“…The NS2B-NS3 protease is a high-priority drug target [17][18][19][20]. Most attempts to develop flavivirus protease inhibitors have focused on the NS3 active site with limited success, possibly due to two of the site's features (reviewed in [21][22][23][24]).…”