In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors (original) (raw)
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European journal of medicinal chemistry, 2017
Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.
Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease
Journal of Medicinal Chemistry, 2020
Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.
European Journal of Medicinal Chemistry, 2016
Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents. We hypothesized that the S 4 subsite of the enzyme may provide an effective means of designing potent and cell permeable inhibitors of the enzyme. We report herein the structure-guided exploration and exploitation of the S 4 subsite of norovirus 3CL protease in the design and synthesis of effective inhibitors of the protease.
Crystal Structure of Inhibitor-Bound GII.4 Sydney 2012 Norovirus 3C-Like Protease
Viruses
Norovirus is the leading cause of viral gastroenteritis worldwide, and there are no approved vaccines or therapeutic treatments for chronic or severe norovirus infections. The structural characterisation of the norovirus protease and drug development has predominantly focused upon GI.1 noroviruses, despite most global outbreaks being caused by GII.4 noroviruses. Here, we determined the crystal structures of the GII.4 Sydney 2012 ligand-free norovirus protease at 2.79 Å and at 1.83 Å with a covalently bound high-affinity (IC50 = 0.37 µM) protease inhibitor (NV-004). We show that the active sites of the ligand-free protease structure are present in both open and closed conformations, as determined by their Arg112 side chain orientation. A comparative analysis of the ligand-free and ligand-bound protease structures reveals significant structural differences in the active site cleft and substrate-binding pockets when an inhibitor is covalently bound. We also report a second molecule of ...
Design, synthesis, and evaluation of inhibitors of Norwalk virus 3C protease
Bioorganic & Medicinal Chemistry Letters, 2011
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.
Frontiers in Chemistry
Human noroviruses (NV) are the most prevalent cause of sporadic and pandemic acute gastroenteritis. NV infections cause substantial morbidity and death globally, especially amongst the aged, immunocompromised individuals, and children. There are presently no authorized NV vaccines, small-molecule therapies, or prophylactics for humans. NV 3 C L protease (3CLP) has been identified as a promising therapeutic target for anti-NV drug development. Herein, we employed a structure-based virtual screening method to screen a library of 700 antiviral compounds against the active site residues of 3CLP. We report three compounds, Sorafenib, YM201636, and LDC4297, that were revealed to have a higher binding energy (BE) value with 3CLP than the control (Dipeptidyl inhibitor 7) following a sequential screening, in-depth molecular docking and visualization, physicochemical and pharmacological property analysis, and molecular dynamics (MD) study. Sorafenib, YM201636, and LDC4297 had BEs of -11.67, -...
European journal of medicinal chemistry, 2018
Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.
Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors
Bioorganic & Medicinal Chemistry Letters, 2013
Keywords: Viral 3C and 3C-like protease inhibitors Norovirus Human rhinovirus Severe acute respiratory syndrome coronavirus Coronavirus 229E a b s t r a c t A class of tripeptidyl transition state inhibitors containing a P1 glutamine surrogate, a P2 leucine, and a P3 arylalanines, was found to potently inhibit Norwalk virus replication in enzyme and cell based assays.
Structural and antiviral studies of the human norovirus GII.4 protease
Biochemistry, 2019
Noroviruses are single-stranded RNA viruses. They encode a protease that cleaves a viral polyprotein at specific sites to produce mature viral proteins. In addition, the protease also binds to viral RNA, and thus is thought to regulate viral replication. However, to date no structural information is available for protease-substrate complexes that might explain the interactions made by peptide residues P'-side of cleavage junctions or RNA. Here I report the work carried out to characterize these interactions in human norovirus protease using X-ray crystallography. The protease was successfully expressed, purified and the crystallization conditions were optimized to grow crystals for structure determination. Unfortunately, RNA and peptide electron density were not observed in co-crystal structures. The packing of protease molecules in one of the crystal forms shows the interaction of protease C-terminal residues with the peptide-binding groove of a neighboring molecule in the crystal, thereby providing the view of a protease-product complex. iii Acknowledgments It would not have been possible to work on this project without the support and help of people around me. First, I would like to thank my family for their unconditional support. Then there are my friends Saad Rajput, Saad Amjad, Mujeeb Mufti and Alexander Carleton, who made graduate life fun and were there for me whenever I needed them.