Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review
Abstract
:1. Introduction
2. Structure and Role of NS3 and NS3 Protease Domain in Flavivirus Replication
3. Structure and Role of NS2B and NS2B Hydrophilic Domain in Flavivirus Replication
4. Dengue Virus (DENV)
5. Yellow Fever Virus (YFV)
6. Zika Virus (ZIKV)
7. Japanese Encephalitis Virus (JEV)
8. West Nile Virus (WNV)
9. Interaction of Flavivirus NS2B-NS3 Proteases with Cellular Proteins
10. Interactions of Flavivirus NS3 with Host Cell NPC and Nucleus
11. Characterization of Flavivirus NS2B-NS3 Proteases
12. NS2B-NS3 Proteases as a Potential Viral Inhibition Drug Target
13. Proposing Role of STING in Development of In Vitro and In Vivo Models for Studying Flavivirus Pathogenesis and Antiviral Drug Screens
14. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Flavivirus | Cleavage/Substrate Sites | Reference | ||||
---|---|---|---|---|---|---|
Capsid C | NS2A/NS2B | NS2B/NS3 | NS3/NS4A | NS4B/NS5 | ||
JEV | VNKRGRKQNKRJ ↓GGNEGS | NPNKKR ↓GWPATE | LKTTKR ↓GGVFWD | FAAGKR ↓SAISFI | KPSLKR ↓GRPGGR | [151] |
NKRGRKQNKR ↓GGNEGSIMWL | GLMVCNPNKKR ↓GWPAT EFLSA | GYWLTLKTTKR ↓GGVFWDTPSP | WFKDFAAGKR ↓SAVSFIEVLG | - | [32] | |
YFV | LSSRKRR ↓SHDVLT | RIFGRR ↓SIPVNE | VRGARR ↓SGDVLM | FAEGRR ↓GAAEVL | MKTGRR ↓GSANGK | [152] |
WNV | INBBSTKQKKS ↓GGTAGF | OPNRKR ↓GWPATE | LQYTKR ↓GGVLWD | FASGKR ↓SQIGLV | KPGLKR ↓GGAKGR | [153,154,155,156] |
- | DPNRKR ↓GW | LQYTKR ↓GG | FASGKR ↓SQ | KPGLKR ↓GG | [122] | |
ZIKV | KERKRR ↓GADTSIGI | TRSGKR ↓SWPPSEVL | VKTGKR ↓SGALWDVP | FAAGKR ↓GAALGVME | GLVKRR ↓GGGTGETL | [127,157] |
DENV1 | MNRRKR ↓SVTMLL | - | - | - | - | [158] |
DENV2 | LNRRRR ↓TAGMII | RTSKKR ↓SWPLNE | EVKKQR ↓AGVLWD | FAAGRK ↓SLTLNL | - | [159] |
DENV3 | INKRKK ↓TSLCLM | - | - | - | - | [160] |
DENV4 | LNGRKR ↓STITLL | KGASRR ↓SWPLNE | QVKTQR ↓SGALWD | FASGRK ↓SITLDI | AQTPRR ↓GTGTTG | [161,162] |
Flavivirus | Optimum Buffers and Reaction Conditions | Reference | ||||
---|---|---|---|---|---|---|
Tris-HCl | NaCl | Glycerol | Temp | pH | ||
DENV | 50 mM | 50 mM | 35% | 37 °C | 8.5 | [67] |
JEV | 50 mM | 25 mM | 30% | 37 °C | 9.5 | [75] |
WNV | 200 mM | 13.5 mM | 30% | 37 °C | 9.5 | [163] |
ZIKV | 20 or 50 mM | 150 mM | 10 or 20% | 37 °C | 8.5 | [50,164,165] |
Tris-HCl | Acetic Acid | Glycine | Temp | pH | ||
YFV | 75 mM | 25 mM | 25 mM | 37 °C | 7.0 | [166] |
Sr No | Flavivirus | Antivirals Screened by Targeting NS2B/NS3 Proteases | Mechanism | Reference |
---|---|---|---|---|
1 | WNV (West Nile Virus) | Benzoyl-norleucine-lysine-arginine-arginine (Bz-nKRR) tetrapeptide aldehyde | C-terminal electrophile incorporation | [177] |
Cationic tripeptides (along with nonpeptide cap) | [176] | |||
Peptide–boronic acid inhibitors | [173] | |||
Benzyl ethers of 4-hydroxyphenylglycine | N-terminal capping moiety optimization | [172] | ||
Bz-Arg-Lys-X-NH | [178] | |||
Peptide-hybrids based on 2,4-thiazolidinedione scaffolds containing nonpolar groups | [179] | |||
Benzyl ethers of 4-hydroxyphenylglycine | P1 and P2 basic residue modulation | [172] | ||
Aprotinin | Noncompetitive inhibitors | [117] | ||
Palmatine (Coptis chinensis) | [180] | |||
Derivatives of Guanidinylated 2,5-dideoxystreptamine | Competitive inhibitors | [181] | ||
Benzoyl-norleucine-lysine-arginine- arginine (Bz-nKRR) tetrapeptide aldehyde | Aldehydic inhibitors | [177] | ||
Cationic tripeptides (along with nonpeptide cap) | [176] | |||
Aprotinin | Stearic hindrance of active site | [175] | ||
D-arginine-based 9–12-mer peptides | Mechanism yet to be determined | [175] | ||
Furin | [182] | |||
C-Terminal Electrophile incorporation | Peptide–boronic acid inhibitors | [173] | ||
2 | DENV (Dengue Virus) | Tetrapeptide: Bz-Nle-Lys-Arg-Arg-B(OH)2 (boronic acid analogue) | C-Terminal electrophile incorporation N-terminal capping moiety optimization | [170] |
Benzyl ethers of 4-hydroxyphenylglycine | [172] | |||
Bz-Arg-Lys-X-NH | N-terminal capping moiety optimization P1 and P2 basic residue modulation | [178] | ||
Rhodanines and Thiazolidinediones | [183] | |||
Benzyl ethers of 4-hydroxyphenylglycine | [172] | |||
Plectasin | Noncompetitive inhibition | [184] | ||
Substitution of Arg with unnatural Arg motifs in the P2 | P1 and P2 basic residue modulation Aldehydic inhibitors(against DENV 2) | [185] | ||
Benzoyl-norleucine-lysine-arginine- arginine (Bz-nKRR) tetrapeptide aldehyde | [177] | |||
Cationic tripeptides (along with nonpeptide cap) | Aldehydic inhibitors (against DENV 2) | [176] | ||
Cyclopentapeptide (CKRKC) | Mechanism yet to be determined | [186] | ||
BP-2109 | [187] | |||
BP13944 | [188] | |||
BT 24 (quinoline compound) | [189] | |||
Aminobenzamide | [190] | |||
2,5,6-trisubstituted pyrazine compounds | [191] | |||
Furin | [182] | |||
Protegrin-1 | [192] | |||
Retrocyclin-1 | [193] | |||
Chalcone derivatives (DENV-2) | [194] | |||
Flavonoids (fingerroot) (DENV-2) | [194] | |||
Tyrothricin | Competitive inhibition | [195] | ||
Derivatives of Guanidinylated 2,5-dideoxystreptamine | [181] | |||
Retrotripeptides: R-Arg-Lys-Nle-NH2 Ivermectin Selamectin Benezethonium chloride | Mixed inhibition | [196] [195] | ||
Peptide-boronic acid | C-terminal electrophile incorporation | [173] | ||
3 | ZIKV (Zika Virus) | Peptidomimetic boronic acid | Formation of salt bridge with Asp83 of NS2B | [95] |
Bromocriptine | Mechanism yet to be determined | [197] | ||
Novobiocin | [198] | |||
Hydroxychloroquine | [199] | |||
Erythrosin B | [200] | |||
Theaflavin-3,3′-digallate | [201] | |||
9b (HIV protease inhibitor) | [202] | |||
2,5,6-trisubstituted pyrazine compounds | [191] | |||
Aprotinin | [75] | |||
4 | JEV (Japanese Encephalitis Virus) | NSC135618 | Inhibits the conformational change of NS2B (allosteric inhibitor) | [203] |
5 | YFV (Yellow fever Virus) | Erythrosin B | Mechanism yet to be determined | [200] |
Animal Models for Studying Dengue Virus (DENV) | |||||
---|---|---|---|---|---|
Animal Type | Model | Study Conducted/Findings | Reference | ||
Nonhuman Primates | Rhesus macaquesa | Inactivated vaccine (DENV-II). | [232] | ||
Expression of G protein in Vaccinia virus (DENV-2). | [233] | ||||
DNA vaccine (encoding Pr-M and E) of DENV-2. | [234] | ||||
DENV-I vaccine. | [235] | ||||
Tetravalent vaccine expressed in Adenovirus. | [236] | ||||
Tetravalent DNA vaccine (chimeric). | [237] | ||||
Mutant DENV (live attenuated) vaccine. | [238] | ||||
Inactivated DENV (tetravalent). | [239] | ||||
DNA vaccine. | [240] | ||||
Cynomolgous macaques | Live attenuated and recombinant vaccine comparison. | [241] | |||
Chimeric DENV1/2 vaccine. | [242] | ||||
Recombinant DENV. | [243] | ||||
Recombinant protein (DENV 1–4). | [244] | ||||
Tetravalent DENV vaccine (chimeric). | [245] | ||||
Tetravalent DENV vaccine (live attenuated). | [246] | ||||
DENV-2 virus-like particles. | [247] | ||||
Mice | A/J | DENV-2 caused thrombocytopenia. | [248] | ||
AG129 (do not have type I and II Interferon receptors) | DENV caused neurological manifestations leading to death. | [249] | |||
DENV infection caused systemic infection and vascular leakage, leading to death. | [250] | ||||
DENV infection resulted in splenomegaly. | [251] | ||||
IFNAR−/− (Lack of IFN type I receptors; background of C57BL/6 mice) | DENV-2 infection resulted in viral growth in small intestine, liver, and bone marrow, resulting in death. | [252] | |||
Cardif −/− | DENV infection in mice resulted in viral growth in lymph nodes, bone marrow, and spleen. | [253] | |||
STAT 1 −/− | DENV infection resulted in viral growth in kidney, liver, and small intestine; however, the mice survived. | [254] | |||
STAT 2 −/− | DENV infection resulted in viral growth in kidney, liver, and small intestine; however, the mice survived. | ||||
STAT 1 −/− STAT 2 −/− (Lack STAT 1 and 2 proteins) | DENV infection resulted in higher viral titers in serum, kidney, liver, small intestine, and spleen, and mice death occurred. | ||||
STAT1−/−/ IFNAR−/− (Lack of STAT1 and type I IFN receptor) | DENV infection resulted in higher viral titers in serum, kidney, liver, small intestine, and spleen, and mice death occurred. | ||||
STAT1−/−/ IFNGR−/− (Lack of STAT1 and type II IFN receptor) | Mice survived | ||||
Animal Models for Studying Yellow Fever Virus (YFV) | |||||
Animal Type | Model | Study Conducted/Findings | Reference | ||
Nonhuman Primates | Cynomolgous macaques | YFV-DENV(1–4) vaccine | [255] | ||
YFV-DENV Chimeric vaccine | [256] | ||||
Models for Studying Flavivirus NS2B-NS3 Proteases | |||||
Virus Type | Cells | Animal Spp. | Outcome | Reference | |
DENV ZIKV JEV WNV | Dermal fibroblasts (DFs) | Great apes (Pan paniscus, Pan troglodytes, Pongo pygmaeus Gorilla gorilla) | Dermal fibroblasts (DFs) demonstrated increased mice susceptibility to infection by Flaviviruses. | [215] | |
Old World monkeys (Macaca nemestrina, Papio anubis, Macaca mulatta) | Increased mice susceptibility to infection by Flaviviruses. | ||||
New world monkeys (Saimiri sciureus) | Increased mice susceptibility to infection by Flaviviruses. | ||||
Mice (Tmem173Gt) | STING disruption increased mice susceptibility to infection by Flaviviruses; however, they could not develop serious infection (underlines the role of redundant pathways in viral replication dynamics). |
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Wahaab, A.; Mustafa, B.E.; Hameed, M.; Stevenson, N.J.; Anwar, M.N.; Liu, K.; Wei, J.; Qiu, Y.; Ma, Z. Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review. Viruses 2022, 14, 44. https://doi.org/10.3390/v14010044
Wahaab A, Mustafa BE, Hameed M, Stevenson NJ, Anwar MN, Liu K, Wei J, Qiu Y, Ma Z. Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review. Viruses. 2022; 14(1):44. https://doi.org/10.3390/v14010044
Chicago/Turabian StyleWahaab, Abdul, Bahar E Mustafa, Muddassar Hameed, Nigel J. Stevenson, Muhammad Naveed Anwar, Ke Liu, Jianchao Wei, Yafeng Qiu, and Zhiyong Ma. 2022. "Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review" Viruses 14, no. 1: 44. https://doi.org/10.3390/v14010044
APA StyleWahaab, A., Mustafa, B. E., Hameed, M., Stevenson, N. J., Anwar, M. N., Liu, K., Wei, J., Qiu, Y., & Ma, Z. (2022). Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review. Viruses, 14(1), 44. https://doi.org/10.3390/v14010044