Please wait a minute...
Shopping Cart Email List Chinese
Advanced Search Fig/Tab
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Featured Articles  |  Most Downloaded  |  Most Reading
Online Submission Subscribe to Our RSS Content Feed
Front. Med.    2017, Vol. 11 Issue (4) : 449-461    https://doi.org/10.1007/s11684-017-0589-5
REVIEW
Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses
Xiaohuan Wang1, Peng Zou1, Fan Wu1, Lu Lu1(), Shibo Jiang1,2()
1. Shanghai Public Health Clinical Center & Key Laboratory of Medical Molecular Virology of MOE/MOH of School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
2. Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
 Download: PDF(429 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

In recent years, unexpected outbreaks of infectious diseases caused by emerging and re-emerging viruses have become more frequent, which is possibly due to environmental changes. These outbreaks result in the loss of life and economic hardship. Vaccines and therapeutics should be developed for the prevention and treatment of infectious diseases. In this review, we summarize and discuss the latest progress in the development of small-molecule viral inhibitors against highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus, Ebola virus, and Zika virus. These viruses can interfere with the specific steps of viral life cycle by blocking the binding between virus and host cells, disrupting viral endocytosis, disturbing membrane fusion, and interrupting viral RNA replication and translation, thereby demonstrating potent therapeutic effect against various emerging and re-emerging viruses. We also discuss some general strategies for developing small-molecule viral inhibitors.
Keywords emerging and re-emerging viruses      small-molecule inhibitor      coronavirus      Ebola virus      Zika virus      life cycle     
Corresponding Author(s): Lu Lu,Shibo Jiang   
Just Accepted Date: 30 October 2017   Online First Date: 22 November 2017    Issue Date: 04 December 2017
 Cite this article:   
Xiaohuan Wang,Peng Zou,Fan Wu, et al. Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses[J]. Front. Med., 2017, 11(4): 449-461.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-017-0589-5
https://academic.hep.com.cn/fmd/EN/Y2017/V11/I4/449
Fig.1  Schematic diagram of the life cycle of coronaviruses (SARS-CoV and MERS-CoV). Small-molecule viral inhibitors are classified into specific groups according to their different mechanisms of action. ACE2, angiotensin-converting enzyme 2; hDPP4, human dipeptidyl peptidase 4.
Virus Inhibitor Testing model Efficacy (IC50) Ref.
Inhibitors blocking the binding between virus and host cells
SARS-CoV Peptide S471-503 In vitro 41.6 µmol/L [24]
Peptide P6 In vitro 100 nmol/L [25]
Inhibitors disrupting endocytosis
SARS-CoV
MERS-CoV		 Chlorpromazine In vitro 8.8 µmol/L; 4.9 µmol/L [26]
Inhibitors disturbing membrane fusion
SARS-CoV CP-1 In vitro 19 µmol/L [28]
Oxocarbazate In vitro 273 nmol/L [35]
Tetra-O-galloyl-β-D-glucose In vitro 4.5 µmol/L [27]
MERS-CoV HR2P In vitro:
293T cells
Vero cells
Calu-3 cells
HFL cells		 　
0.8 mmol/L
0.6 mmol/L
0.6 mmol/L
13.9 mmol/L		 [18]
HR2P-M2 In vitro 0.55 mmol/L [29 , 30]
In vivo Ad5-hDPP4-transduced ?mouse Decreasing viral titer in lung tissue
SARS-CoV
MERS-CoV
　		 P9 In vitro 5 mg/mL [31]
ADS-J1 In vitro 0.6 and 3.89 mmol/L [32 , 33]
E-64-D In vitro 0.76 and 1.28 mmol/L [36]
Inhibitors interrupting viral RNA replication and translation
SARS-CoV siSC2-5 In vivo
NHPa		 Reducing viral copies in ?respiratory tract [38]
Compound 5c In vitro 0.35 mmol/L [41 , 42]
MERS-CoV Ribavirin In vitro 9.99 mg/mL [39]
SARS-CoV
MERS-CoV		 SSYA10-001 In vitro 7 mmol/L; 25 mmol/L [40]
Inhibitors with undefined mechanism
SRAS-CoV
MERS-CoV		 Tamoxifen citrate In vitro 10.12 and 92.89 mmol/L [36]
Toremifene citrate In vitro 11.97 and 12.92 mmol/L
Gemcitabine hydrochloride In vitro 1.2 and 4.9 mmol/L
Tab.1  Small-molecule viral inhibitors against SARS-CoV and/or MERS-CoV
Fig.2  Schematic diagram of the life cycle of Ebola virus. Small-molecule viral inhibitors are classified into specific groups according to their different mechanisms of action. TIM-1, T cell immunoglobulin and mucin domain 1; NPC1, Niemann–Pick C1.
Inhibitor name Testing model Efficacy (IC50) Ref.
Inhibitors disrupting endocytosis
5-(N-ethyl-N-isopropyl) amiloride In vitro <50 mmol/L [53]
Inhibitors disturbing membrane fusion
LJ001 In vivo
BALB/c mouse		 Protection rate: 80% [54]
Tat-Ebo In vitro <50 mmol/L [55]
Oxocarbazate In vitro 193 nmol/L [35]
Compound 7 In vitro 10 mmol/L [56]
Bepridil In vitro:
Vero E6 cells
HepG2 cells		 　
5.08 mmol/L
3.21 mmol/L		 [58]
In vivo
C57BL/6 mouse		 Protection rate: 100%
Sertraline In vitro
Vero E6 cells
HepG2 cells		 　
3.13 mmol/L
1.44 mmol/L
In vivo
C57BL/6 mouse		 Protection rate: 70%
Inhibitors interrupting viral RNA replication and translation
BCX4430 In vitro 11.8 mmol/L [61]
Favipiravir In vitro 67 mmol/L [60]
In vivo IFNAR- / - C57BL/6 mouse Protection rate: 100%
Atovaquone In vitro
Vero E6 cells		 　
0.44 mmol/L		 [58 , 62 – 64]
Azacitidine In vitro:
Vero E6 cells
HepG2 cells		 　
8.97 mmol/L
10.3 mmol/L
Mycophenolate mofetil In vitro
HepG2 cells		 　
0.29 mmol/L
TKM-Ebola In vivo
NHP		 Protection rate: 66% [66]
AVI-6002 In vivo
NHP		 Protection rate: 60% [65]
Inhibitors with undefined mechanism
Strophanthin In vitro:
Vero E6 cells
HepG2 cells		 　
0.035 mmol/L
0.021 mmol/L		 [58]
Tab.2  Small-molecule viral inhibitors against Ebola virus
Fig.3  Schematic diagram of the life cycle of Zika virus. Small-molecule viral inhibitors are classified into specific groups according to their different mechanisms of action.
Inhibitor name Testing model Efficacy (IC50) Ref.
Inhibitors blocking the binding between virus and host cells
Peptide Z2 In vitro:
BHK21 cells
Vero cells		 　
1.75 mmol/L
3.69 mmol/L		 [73]
In vivo:
A129 mouse
AG6 mouse		 Protection rate: 75% and 67%
Curcumin In vitro 1.90 mmol/L [75]
Inhibitors disrupting endocytosis
Nanchangmycin In vitro:
Human HBMECs
Human U2OS Cells		 　
0.4 mmol/L
0.1 mmol/L		 [76]
Inhibitors disturbing membrane fusion
Chloroquine In vitro 50 mmol/L [77]
In vivo
Swiss mouse		 Inhibiting ZIKV infection in mouse ?neurospheres
Niclosamide In vitro 0.2 µmol/L [78]
25-Hydroxycholesterol In vitro 188 nmol/L [79]
In vivo:
A129 mouse
NHP		 Reducing viremia and improving ?survival
Reducing viremia
Inhibitors interrupting viral RNA replication and translation
Compounds 1-10 In vitro <50 µmol/L [80]
Sofosbuvir In vitro 8.3 µmol/L [83]
DMB213 In vitro 4.6 µmol/L
Temoporfin In vitro 0.024 µmol/L [84]
In vivo
BALB/C mouse
A129 mouse		 Reducing viremia
Protection rate: 83%
7-Deaza-2?-C-methyladenosine In vivo
AG129 mouse		 Delaying Zika diseases [85]
2?-C-methylated nucleosides In vitro 2.7–47.3 µmol/L [86]
NITD008 In vitro 137–241 nmol/L [87]
In vivo
A129 mouse		 Protection rate: 50%
Inhibitors with undefined mechanism
Emricasan In vitro:
SNB-19 cells
Astrocyte cells
hNPC cells		 　
0.87 µmol/L
4.11 µmol/L
3.88 µmol/L 		[78]
Ex vivo
3D brain organoids		 Showing neuroprotective activity for hNPC cells
Tab.3  Small-molecule viral inhibitors against Zika virus
Fig.4  Schematic diagram of general strategies for developing small-molecule viral inhibitors. The strategies include the (1) inhibition of viral entry by blocking the formation of six-helix bundle, (2) inhibition of viral replication by targeting the viral RNA-dependent RNA polymerase, (3) inhibition of viral replication by targeting cellular protease, and (4) screening of clinical drug library for viral entry and replication inhibitors. ZIKV, Zika virus; YFV, yellow fever virus; CHIKV, Chikungunya virus; H7N9, H7N9 influenza A virus; SARS-CoV, severe acute respiratory syndrome coronavirus; MERS-CoV, Middle East respiratory syndrome coronavirus; EBOV, Ebola virus; HIV, human immunodeficiency virus.
1 OG Pybus, AJ Tatem, P Lemey. Virus evolution and transmission in an ever more connected world. Proc Biol Sci 2015; 282(1821): 20142878.
2 T Kuiken, RA Fouchier, M Schutten, GF Rimmelzwaan, G van Amerongen, D van Riel, JD Laman, T de Jong, G van Doornum, W Lim, AE Ling, PK Chan, JS Tam, MC Zambon, R Gopal, C Drosten, S van der Werf, N Escriou, JC Manuguerra, K Stöhr, JS Peiris, AD Osterhaus. Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome. Lancet 2003; 362(9380): 263–270
https://doi.org/10.1016/S0140-6736(03)13967-0 pmid: 12892955
3 AM Zaki, S van Boheemen, TM Bestebroer, AD Osterhaus, RA Fouchier. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367(19): 1814–1820
https://doi.org/10.1056/NEJMoa1211721 pmid: 23075143
4 L Lu, Q Liu, L Du, S Jiang. Middle East respiratory syndrome coronavirus (MERS-CoV): challenges in identifying its source and controlling its spread. Microbes Infect 2013; 15(8-9): 625–629
https://doi.org/10.1016/j.micinf.2013.06.003 pmid: 23791956
5 World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV).
6 World Health Organization. Ebola Situation Reports.
7 World Health Organization. Media centre: Zika virus.
8 W Ma, S Li, S Ma, L Jia, F Zhang, Y Zhang, J Zhang, G Wong, S Zhang, X Lu, M Liu, J Yan, W Li, C Qin, D Han, C Qin, N Wang, X Li, GF Gao. Zika virus causes testis damage and leads to male infertility in mice. Cell 2016; 167(6): 1511–1524. e1510
9 C Li, D Xu, Q Ye, S Hong, Y Jiang, X Liu, N Zhang, L Shi, CF Qin, Z Xu. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell 2016; 19(1): 120–126
https://doi.org/10.1016/j.stem.2016.04.017 pmid: 27179424
10 A Wang, S Thurmond, L Islas, K Hui, R Hai. Zika virus genome biology and molecular pathogenesis. Emerg Microbes Infect 2017; 6(3): e13
https://doi.org/10.1038/emi.2016.141 pmid: 28325921
11 G Calvet, RS Aguiar, ASO Melo, SA Sampaio, I de Filippis, A Fabri, ESM Araujo, PC de Sequeira, MCL de Mendonça, L de Oliveira, DA Tschoeke, CG Schrago, FL Thompson, P Brasil, FB Dos Santos, RMR Nogueira, A Tanuri, AMB de Filippis. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016; 16(6): 653–660
https://doi.org/10.1016/S1473-3099(16)00095-5 pmid: 26897108
12 FT Goodfellow, B Tesla, G Simchick, Q Zhao, T Hodge, MA Brindley, SL Stice. Zika virus induced mortality and microcephaly in chicken embryos. Stem Cells Dev 2016; 25(22): 1691–1697
https://doi.org/10.1089/scd.2016.0231 pmid: 27627457
13 L Schuler-Faccini, EM Ribeiro, IM Feitosa, DD Horovitz, DP Cavalcanti, A Pessoa, MJ Doriqui, JI Neri, JM Neto, HY Wanderley, M Cernach, AS El-Husny, MV Pone, CL Serao, MT Sanseverino; Brazilian Medical Genetics Society–Zika Embryopathy Task Force. Possible association between Zika virus infection and microcephaly — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016; 65(3): 59–62
https://doi.org/10.15585/mmwr.mm6503e2 pmid: 26820244
14 E De Clercq, G Li. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 2016; 29(3): 695–747
https://doi.org/10.1128/CMR.00102-15 pmid: 27281742
15 CA de Haan, PJ Rottier. Molecular interactions in the assembly of coronaviruses. Adv Virus Res 2005; 64: 165–230
https://doi.org/10.1016/S0065-3527(05)64006-7 pmid: 16139595
16 W Li, MJ Moore, N Vasilieva, J Sui, SK Wong, MA Berne, M Somasundaran, JL Sullivan, K Luzuriaga, TC Greenough, H Choe, M Farzan. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450–454
https://doi.org/10.1038/nature02145 pmid: 14647384
17 S Matsuyama, M Ujike, S Morikawa, M Tashiro, F Taguchi. Protease-mediated enhancement of severe acute respiratory syndrome coronavirus infection. Proc Natl Acad Sci USA 2005; 102(35): 12543–12547
https://doi.org/10.1073/pnas.0503203102 pmid: 16116101
18 L Lu, Q Liu, Y Zhu, KH Chan, L Qin, Y Li, Q Wang, JF Chan, L Du, F Yu, C Ma, S Ye, KY Yuen, R Zhang, S Jiang. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014; 5: 3067
pmid: 24473083
19 S Xia, Q Liu, Q Wang, Z Sun, S Su, L Du, T Ying, L Lu, S Jiang. Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein. Virus Res 2014; 194: 200–210
https://doi.org/10.1016/j.virusres.2014.10.007 pmid: 25451066
20 L Du, Y He, Y Zhou, S Liu, BJ Zheng, S Jiang. The spike protein of SARS-CoV—a target for vaccine and therapeutic development. Nat Rev Microbiol 2009; 7(3): 226–236
https://doi.org/10.1038/nrmicro2090 pmid: 19198616
21 VS Raj, H Mou, SL Smits, DH Dekkers, MA Müller, R Dijkman, D Muth, JA Demmers, A Zaki, RA Fouchier, V Thiel, C Drosten, PJ Rottier, AD Osterhaus, BJ Bosch, BL Haagmans. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495(7440): 251–254
https://doi.org/10.1038/nature12005 pmid: 23486063
22 K Shirato, M Kawase, S Matsuyama. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol 2013; 87(23): 12552–12561
https://doi.org/10.1128/JVI.01890-13 pmid: 24027332
23 Q Liu, S Xia, Z Sun, Q Wang, L Du, L Lu, S Jiang. Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry. Antimicrob Agents Chemother 2015; 59(1): 742–744
https://doi.org/10.1128/AAC.03977-14 pmid: 25331705
24 H Hu, L Li, RY Kao, B Kou, Z Wang, L Zhang, H Zhang, Z Hao, WH Tsui, A Ni, L Cui, B Fan, F Guo, S Rao, C Jiang, Q Li, M Sun, W He, G Liu. Screening and identification of linear B-cell epitopes and entry-blocking peptide of severe acute respiratory syndrome (SARS)-associated coronavirus using synthetic overlapping peptide library. J Comb Chem 2005; 7(5): 648–656
https://doi.org/10.1021/cc0500607 pmid: 16153058
25 DP Han, A Penn-Nicholson, MW Cho. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology 2006; 350(1): 15–25
https://doi.org/10.1016/j.virol.2006.01.029 pmid: 16510163
26 AH de Wilde, D Jochmans, CC Posthuma, JC Zevenhoven-Dobbe, S van Nieuwkoop, TM Bestebroer, BG van den Hoogen, J Neyts, EJ Snijder. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014; 58(8): 4875–4884
https://doi.org/10.1128/AAC.03011-14 pmid: 24841269
27 L Yi, Z Li, K Yuan, X Qu, J Chen, G Wang, H Zhang, H Luo, L Zhu, P Jiang, L Chen, Y Shen, M Luo, G Zuo, J Hu, D Duan, Y Nie, X Shi, W Wang, Y Han, T Li, Y Liu, M Ding, H Deng, X Xu. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004; 78(20): 11334–11339
https://doi.org/10.1128/JVI.78.20.11334-11339.2004 pmid: 15452254
28 S Liu, G Xiao, Y Chen, Y He, J Niu, CR Escalante, H Xiong, J Farmar, AK Debnath, P Tien, S Jiang. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 2004; 363(9413): 938–947
https://doi.org/10.1016/S0140-6736(04)15788-7 pmid: 15043961
29 R Channappanavar, L Lu, S Xia, L Du, DK Meyerholz, S Perlman, S Jiang. Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J Infect Dis 2015; 212(12): 1894–1903
https://doi.org/10.1093/infdis/jiv325 pmid: 26164863
30 L Lu, S Xia, T Ying, S Jiang. Urgent development of effective therapeutic and prophylactic agents to control the emerging threat of Middle East respiratory syndrome (MERS). Emerg Microbes Infect 2015; 4(6): e37
https://doi.org/10.1038/emi.2015.37 pmid: 26954884
31 H Zhao, J Zhou, K Zhang, H Chu, D Liu, VK Poon, CC Chan, HC Leung, N Fai, YP Lin, AJ Zhang, DY Jin, KY Yuen, BJ Zheng. A novel peptide with potent and broad-spectrum antiviral activities against multiple respiratory viruses. Sci Rep 2016; 6(1): 22008
https://doi.org/10.1038/srep22008 pmid: 26911565
32 LH Chu, SH Chan, SN Tsai, Y Wang, CH Cheng, KB Wong, MM Waye, SM Ngai. Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): in search of potent SARS-CoV entry inhibitors. J Cell Biochem 2008; 104(6): 2335–2347
https://doi.org/10.1002/jcb.21790 pmid: 18442051
33 G Zhao, L Du, C Ma, Y Li, L Li, VK Poon, L Wang, F Yu, BJ Zheng, S Jiang, Y Zhou. A safe and convenient pseudovirus-based inhibition assay to detect neutralizing antibodies and screen for viral entry inhibitors against the novel human coronavirus MERS-CoV. Virol J 2013; 10(1): 266
https://doi.org/10.1186/1743-422X-10-266 pmid: 23978242
34 G Simmons, DN Gosalia, AJ Rennekamp, JD Reeves, SL Diamond, P Bates. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci USA 2005; 102(33): 11876–11881
https://doi.org/10.1073/pnas.0505577102 pmid: 16081529
35 PP Shah, T Wang, RL Kaletsky, MC Myers, JE Purvis, H Jing, DM Huryn, DC Greenbaum, AB Smith 3rd, P Bates, SL Diamond. A small-molecule oxocarbazate inhibitor of human cathepsin L blocks severe acute respiratory syndrome and ebola pseudotype virus infection into human embryonic kidney 293T cells. Mol Pharmacol 2010; 78(2): 319–324
https://doi.org/10.1124/mol.110.064261 pmid: 20466822
36 J Dyall, CM Coleman, BJ Hart, T Venkataraman, MR Holbrook, J Kindrachuk, RF Johnson, GG Olinger Jr, PB Jahrling, M Laidlaw, LM Johansen, CM Lear-Rooney, PJ Glass, LE Hensley, MB Frieman. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58(8): 4885–4893
https://doi.org/10.1128/AAC.03036-14 pmid: 24841273
37 T Li, Y Zhang, L Fu, C Yu, X Li, Y Li, X Zhang, Z Rong, Y Wang, H Ning, R Liang, W Chen, LA Babiuk, Z Chang. siRNA targeting the leader sequence of SARS-CoV inhibits virus replication. Gene Ther 2005; 12(9): 751–761
https://doi.org/10.1038/sj.gt.3302479 pmid: 15772689
38 BJ Li, Q Tang, D Cheng, C Qin, FY Xie, Q Wei, J Xu, Y Liu, BJ Zheng, MC Woodle, N Zhong, PY Lu. Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat Med 2005; 11(9): 944–951
pmid: 16116432
39 JF Chan, KH Chan, RY Kao, KK To, BJ Zheng, CP Li, PT Li, J Dai, FK Mok, H Chen, FG Hayden, KY Yuen. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013; 67(6): 606–616
https://doi.org/10.1016/j.jinf.2013.09.029 pmid: 24096239
40 AO Adedeji, K Singh, A Kassim, CM Coleman, R Elliott, SR Weiss, MB Frieman, SG Sarafianos. Evaluation of SSYA10-001 as a replication inhibitor of severe acute respiratory syndrome, mouse hepatitis, and Middle East respiratory syndrome coronaviruses. Antimicrob Agents Chemother 2014; 58(8): 4894–4898
https://doi.org/10.1128/AAC.02994-14 pmid: 24841268
41 H Wang, S Xue, H Yang, C Chen. Recent progress in the discovery of inhibitors targeting coronavirus proteases. Virol Sin 2016; 31(1): 24–30
https://doi.org/10.1007/s12250-015-3711-3 pmid: 26920707
42 YM Báez-Santos, SJ Barraza, MW Wilson, MP Agius, AM Mielech, NM Davis, SC Baker, SD Larsen, AD Mesecar. X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. J Med Chem 2014; 57(6): 2393–2412
https://doi.org/10.1021/jm401712t pmid: 24568342
43 T Hoenen, A Groseth, D Falzarano, H Feldmann. Ebola virus: unravelling pathogenesis to combat a deadly disease. Trends Mol Med 2006; 12(5): 206–215
https://doi.org/10.1016/j.molmed.2006.03.006 pmid: 16616875
44 S Mahanty, M Bray. Pathogenesis of filoviral haemorrhagic fevers. Lancet Infect Dis 2004; 4(8): 487–498
https://doi.org/10.1016/S1473-3099(04)01103-X pmid: 15288821
45 A Nanbo, M Imai, S Watanabe, T Noda, K Takahashi, G Neumann, P Halfmann, Y Kawaoka. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog 2010; 6(9): e1001121
https://doi.org/10.1371/journal.ppat.1001121 pmid: 20886108
46 CL Hunt, NJ Lennemann, W Maury. Filovirus entry: a novelty in the viral fusion world. Viruses 2012; 4(2): 258–275
https://doi.org/10.3390/v4020258 pmid: 22470835
47 T Noda, L Kolesnikova, S Becker, Y Kawaoka. The importance of the NP: VP35 ratio in Ebola virus nucleocapsid formation. J Infect Dis 2011; 204(Suppl 3): S878–S883
https://doi.org/10.1093/infdis/jir310 pmid: 21987764
48 T Noda, H Ebihara, Y Muramoto, K Fujii, A Takada, H Sagara, JH Kim, H Kida, H Feldmann, Y Kawaoka. Assembly and budding of Ebolavirus. PLoS Pathog 2006; 2(9): e99
https://doi.org/10.1371/journal.ppat.0020099 pmid: 17009868
49 W Xu, P Luthra, C Wu, J Batra, DW Leung, CF Basler, GK Amarasinghe. Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis. Nat Commun 2017; 8: 15576
https://doi.org/10.1038/ncomms15576 pmid: 28593988
50 H Li, F Yu, S Xia, Y Yu, Q Wang, M Lv, Y Wang, S Jiang, L Lu. Chemically modified human serum albumin potently blocks entry of Ebola pseudoviruses and viruslike particles. Antimicrob Agents Chemother 2017; 61(4): e02168-16
https://doi.org/10.1128/AAC.02168-16 pmid: 28167539
51 H Li, T Ying, F Yu, L Lu, S Jiang. Development of therapeutics for treatment of Ebola virus infection. Microbes Infect 2015; 17(2): 109–117
https://doi.org/10.1016/j.micinf.2014.11.012 pmid: 25498866
52 TR Kleyman, EJ Cragoe Jr. Amiloride and its analogs as tools in the study of ion transport. J Membr Biol 1988; 105(1): 1–21
https://doi.org/10.1007/BF01871102 pmid: 2852254
53 MF Saeed, AA Kolokoltsov, T Albrecht, RA Davey. Cellular entry of Ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog 2010; 6(9): e1001110
https://doi.org/10.1371/journal.ppat.1001110 pmid: 20862315
54 MC Wolf, AN Freiberg, T Zhang, Z Akyol-Ataman, A Grock, PW Hong, J Li, NF Watson, AQ Fang, HC Aguilar, M Porotto, AN Honko, R Damoiseaux, JP Miller, SE Woodson, S Chantasirivisal, V Fontanes, OA Negrete, P Krogstad, A Dasgupta, A Moscona, LE Hensley, SP Whelan, KF Faull, MR Holbrook, ME Jung, B Lee. A broad-spectrum antiviral targeting entry of enveloped viruses. Proc Natl Acad Sci USA 2010; 107(7): 3157–3162
https://doi.org/10.1073/pnas.0909587107 pmid: 20133606
55 EH Miller, JS Harrison, SR Radoshitzky, CD Higgins, X Chi, L Dong, JH Kuhn, S Bavari, JR Lai, K Chandran. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J Biol Chem 2011; 286(18): 15854–15861
https://doi.org/10.1074/jbc.M110.207084 pmid: 21454542
56 A Basu, B Li, DM Mills, RG Panchal, SC Cardinale, MM Butler, NP Peet, H Majgier-Baranowska, JD Williams, I Patel, DT Moir, S Bavari, R Ray, MR Farzan, L Rong, TL Bowlin. Identification of a small-molecule entry inhibitor for filoviruses. J Virol 2011; 85(7): 3106–3119
https://doi.org/10.1128/JVI.01456-10 pmid: 21270170
57 CJ Shoemaker, KL Schornberg, SE Delos, C Scully, H Pajouhesh, GG Olinger, LM Johansen, JM White. Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection. PLoS One 2013; 8(2): e56265
https://doi.org/10.1371/journal.pone.0056265 pmid: 23441171
58 LM Johansen, LE DeWald, CJ Shoemaker, BG Hoffstrom, CM Lear-Rooney, A Stossel, E Nelson, SE Delos, JA Simmons, JM Grenier, LT Pierce, H Pajouhesh, J Lehár, LE Hensley, PJ Glass, JM White, GG Olinger. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci Transl Med 2015; 7(290): 290ra89
https://doi.org/10.1126/scitranslmed.aaa5597 pmid: 26041706
59 V Madelain, L Oestereich, F Graw, TH Nguyen, X de Lamballerie, F Mentré, S Günnther, J Guedj. Ebola virus dynamics in mice treated with favipiravir. Antiviral Res 2015; 123: 70–77
https://doi.org/10.1016/j.antiviral.2015.08.015 pmid: 26343011
60 L Oestereich, A Lüdtke, S Wurr, T Rieger, C Muñoz-Fontela, S Günther. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model. Antiviral Res 2014; 105: 17–21
https://doi.org/10.1016/j.antiviral.2014.02.014 pmid: 24583123
61 TK Warren, J Wells, RG Panchal, KS Stuthman, NL Garza, SA Van Tongeren, L Dong, CJ Retterer, BP Eaton, G Pegoraro, S Honnold, S Bantia, P Kotian, X Chen, BR Taubenheim, LS Welch, DM Minning, YS Babu, WP Sheridan, S Bavari. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature 2014; 508(7496): 402–405
https://doi.org/10.1038/nature13027 pmid: 24590073
62 W Knecht, J Henseling, M Löffler. Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem Biol Interact 2000; 124(1): 61–76
https://doi.org/10.1016/S0009-2797(99)00144-1 pmid: 10658902
63 G Leone, MT Voso, L Teofili, M Lübbert. Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol 2003; 109(1): 89–102
https://doi.org/10.1016/S1521-6616(03)00207-9 pmid: 14585280
64 M Khan, R Dhanwani, IK Patro, PV Rao, MM Parida. Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells. Antiviral Res 2011; 89(1): 1–8
https://doi.org/10.1016/j.antiviral.2010.10.009 pmid: 21070810
65 TK Warren, KL Warfield, J Wells, DL Swenson, KS Donner, SA Van Tongeren, NL Garza, L Dong, DV Mourich, S Crumley, DK Nichols, PL Iversen, S Bavari. Advanced antisense therapies for postexposure protection against lethal filovirus infections. Nat Med 2010; 16(9): 991–994
https://doi.org/10.1038/nm.2202 pmid: 20729866
66 TW Geisbert, AC Lee, M Robbins, JB Geisbert, AN Honko, V Sood, JC Johnson, S de Jong, I Tavakoli, A Judge, LE Hensley, I Maclachlan. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet 2010; 375(9729): 1896–1905
https://doi.org/10.1016/S0140-6736(10)60357-1 pmid: 20511019
67 Z Wang, P Wang, J An. Zika virus and Zika fever. Virol Sin 2016; 31(2): 103–109
https://doi.org/10.1007/s12250-016-3780-y pmid: 27129450
68 L Meertens, A Labeau, O Dejarnac, S Cipriani, L Sinigaglia, L Bonnet-Madin, T Le Charpentier, ML Hafirassou, A Zamborlini, VM Cao-Lormeau, M Coulpier, D Missé, N Jouvenet, R Tabibiazar, P Gressens, O Schwartz, A Amara. Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell Reports 2017; 18(2): 324–333
https://doi.org/10.1016/j.celrep.2016.12.045 pmid: 28076778
69 K Stiasny, FX Heinz. Flavivirus membrane fusion. J Gen Virol 2006; 87(Pt 10): 2755–2766
https://doi.org/10.1099/vir.0.82210-0 pmid: 16963734
70 Z Yi, Z Yuan, CM Rice, MR MacDonald. Flavivirus replication complex assembly revealed by DNAJC14 functional mapping. J Virol 2012; 86(21): 11815–11832
https://doi.org/10.1128/JVI.01022-12 pmid: 22915803
71 B Zhao, G Yi, F Du, YC Chuang, RC Vaughan, B Sankaran, CC Kao, P Li. Structure and function of the Zika virus full-length NS5 protein. Nat Commun 2017; 8: 14762
https://doi.org/10.1038/ncomms14762 pmid: 28345656
72 S Mukhopadhyay, RJ Kuhn, MG Rossmann. A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 2005; 3(1): 13–22
https://doi.org/10.1038/nrmicro1067 pmid: 15608696
73 Y Yu, YQ Deng, P Zou, Q Wang, Y Dai, F Yu, L Du, NN Zhang, M Tian, JN Hao, Y Meng, Y Li, X Zhou, J Fuk-Woo Chan, KY Yuen, CF Qin, S Jiang, L Lu. A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat Commun 2017; 8: 15672
https://doi.org/10.1038/ncomms15672 pmid: 28742068
74 S Fernando, T Fernando, M Stefanik, L Eyer, D Ruzek. An approach for Zika virus inhibition using homology structure of the envelope protein. Mol Biotechnol 2016; 58(12): 801–806
https://doi.org/10.1007/s12033-016-9979-1 pmid: 27683255
75 BC Mounce, T Cesaro, L Carrau, T Vallet, M Vignuzzi. Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antiviral Res 2017; 142: 148–157
https://doi.org/10.1016/j.antiviral.2017.03.014 pmid: 28343845
76 K Rausch, BA Hackett, NL Weinbren, SM Reeder, Y Sadovsky, CA Hunter, DC Schultz, CB Coyne, S Cherry. Screening bioactives reveals Nanchangmycin as a broad spectrum antiviral active against Zika virus. Cell Reports 2017; 18(3): 804–815
https://doi.org/10.1016/j.celrep.2016.12.068 pmid: 28099856
77 R Delvecchio, LM Higa, P Pezzuto, AL Valadão, PP Garcez, FL Monteiro, EC Loiola, AA Dias, FJ Silva, MT Aliota, EA Caine, JE Osorio, M Bellio, DH O’Connor, S Rehen, RS de Aguiar, A Savarino, L Campanati, A Tanuri. Chloroquine, an endocytosis blocking agent, inhibits Zika virus infection in different cell models. Viruses 2016; 8(12): E322
https://doi.org/10.3390/v8120322 pmid: 27916837
78 M Xu, EM Lee, Z Wen, Y Cheng, WK Huang, X Qian, J Tcw, J Kouznetsova, SC Ogden, C Hammack, F Jacob, HN Nguyen, M Itkin, C Hanna, P Shinn, C Allen, SG Michael, A Simeonov, W Huang, KM Christian, A Goate, KJ Brennand, R Huang, M Xia, GL Ming, W Zheng, H Song, H Tang. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med 2016; 22(10): 1101–1107
https://doi.org/10.1038/nm.4184 pmid: 27571349
79 C Li, YQ Deng, S Wang, F Ma, R Aliyari, XY Huang, NN Zhang, M Watanabe, HL Dong, P Liu, XF Li, Q Ye, M Tian, S Hong, J Fan, H Zhao, L Li, N Vishlaghi, JE Buth, C Au, Y Liu, N Lu, P Du, FX Qin, B Zhang, D Gong, X Dai, R Sun, BG Novitch, Z Xu, CF Qin, G Cheng. 25-Hydroxycholesterol protects host against Zika virus infection and its associated microcephaly in a mouse model. Immunity 2017; 46(3): 446–456
https://doi.org/10.1016/j.immuni.2017.02.012 pmid: 28314593
80 H Lee, J Ren, S Nocadello, AJ Rice, I Ojeda, S Light, G Minasov, J Vargas, D Nagarathnam, WF Anderson, ME Johnson. Identification of novel small molecule inhibitors against NS2B/NS3 serine protease from Zika virus. Antiviral Res 2017; 139: 49–58
https://doi.org/10.1016/j.antiviral.2016.12.016 pmid: 28034741
81 X Cao, Y Li, X Jin, Y Li, F Guo, T Jin. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res 2016; 44(21): 10505–10514
pmid: 27915293
82 P Ramharack, MES Soliman. Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery. J Biomol Struct Dyn 2017 Apr 17 [Epub ahead of print] https://doi.org/10.1080/07391102.2017.1313175
https://doi.org/10.1080/07391102.2017.1313175 pmid: 28351337
83 HT Xu, SA Hassounah, SP Colby-Germinario, M Oliveira, C Fogarty, Y Quan, Y Han, O Golubkov, I Ibanescu, B Brenner, BR Stranix, MA Wainberg. Purification of Zika virus RNA-dependent RNA polymerase and its use to identify small-molecule Zika inhibitors. J Antimicrob Chemother 2017; 72(3): 727–734
pmid: 28069884
84 Z Li, M Brecher, YQ Deng, J Zhang, S Sakamuru, B Liu, R Huang, CA Koetzner, CA Allen, SA Jones, H Chen, NN Zhang, M Tian, F Gao, Q Lin, N Banavali, J Zhou, N Boles, M Xia, LD Kramer, CF Qin, H Li. Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Res 2017; 27(8): 1046–1064
https://doi.org/10.1038/cr.2017.88 pmid: 28685770
85 J Zmurko, RE Marques, D Schols, E Verbeken, SJ Kaptein, J Neyts. The viral polymerase inhibitor 7-deaza-2′-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl Trop Dis 2016; 10(5): e0004695
https://doi.org/10.1371/journal.pntd.0004695 pmid: 27163257
86 K Hercík, J Kozak, M Šála, M Dejmek, H Hřebabecký, E Zborníková, M Smola, D Ruzek, R Nencka, E Boura. Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase. Antiviral Res 2017; 137: 131–133
https://doi.org/10.1016/j.antiviral.2016.11.020 pmid: 27902932
87 YQ Deng, NN Zhang, CF Li, M Tian, JN Hao, XP Xie, PY Shi, CF Qin. Adenosine analog NITD008 is a potent inhibitor of Zika virus. Open Forum Infect Dis 2016; 3(4): ofw175
https://doi.org/10.1093/ofid/ofw175 pmid: 27747251
88 X Xie, J Zou, C Shan, Y Yang, DB Kum, K Dallmeier, J Neyts, PY Shi. Zika virus replicons for drug discovery. EBioMedicine 2016; 12: 156–160
https://doi.org/10.1016/j.ebiom.2016.09.013 pmid: 27658737
89 L Cui, P Zou, E Chen, H Yao, H Zheng, Q Wang, JN Zhu, S Jiang, L Lu, J Zhang. Visual and motor deficits in grown-up mice with congenital Zika virus infection. EBioMedicine 2017; 20: 193–201
https://doi.org/10.1016/j.ebiom.2017.04.029 pmid: 28583742
90 J Zou, PY Shi. Adulthood sequelae of congenital Zika virus infection in mice. EBioMedicine 2017; 20: 11–12
https://doi.org/10.1016/j.ebiom.2017.05.005 pmid: 28487052
91 L Lu, F Yu, L Cai, AK Debnath, S Jiang. Development of small-molecule HIV entry inhibitors specifically targeting gp120 or gp41. Curr Top Med Chem 2016; 16(10): 1074–1090
https://doi.org/10.2174/1568026615666150901114527 pmid: 26324044
92 S Jiang, K Lin, N Strick, AR Neurath. HIV-1 inhibition by a peptide. Nature 1993; 365(6442): 113
https://doi.org/10.1038/365113a0 pmid: 8371754
93 JP Lalezari, K Henry, M O’Hearn, JS Montaner, PJ Piliero, B Trottier, S Walmsley, C Cohen, DR Kuritzkes, JJ Jr Eron, J Chung, R DeMasi, L Donatacci, C Drobnes, J Delehanty, M Salgo; TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348(22): 2175–2185
https://doi.org/10.1056/NEJMoa035026 pmid: 12637625
94 S Su, Q Wang, W Xu, F Yu, C Hua, Y Zhu, S Jiang, L Lu. A novel HIV-1 gp41 tripartite model for rational design of HIV-1 fusion inhibitors with improved antiviral activity. AIDS 2017; 31(7): 885–894
https://doi.org/10.1097/QAD.0000000000001415 pmid: 28121713
[1] Weibao Song, Hongjuan Zhang, Yu Zhang, Rui Li, Yanxing Han, Yuan Lin, Jiandong Jiang. Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection[J]. Front. Med., 2021, 15(3): 404-415.
[2] Dongsheng Wang, Binqing Fu, Zhen Peng, Dongliang Yang, Mingfeng Han, Min Li, Yun Yang, Tianjun Yang, Liangye Sun, Wei Li, Wei Shi, Xin Yao, Yan Ma, Fei Xu, Xiaojing Wang, Jun Chen, Daqing Xia, Yubei Sun, Lin Dong, Jumei Wang, Xiaoyu Zhu, Min Zhang, Yonggang Zhou, Aijun Pan, Xiaowen Hu, Xiaodong Mei, Haiming Wei, Xiaoling Xu. Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial[J]. Front. Med., 2021, 15(3): 486-494.
[3] Xiaofang Cai, Hanlan Jiang, Simin Zhang, Shengying Xia, Wenhui Du, Yaoling Ma, Tao Yu, Wenbin Li. Clinical manifestations and pathogen characteristics in children admitted for suspected COVID-19[J]. Front. Med., 2020, 14(6): 776-785.
[4] Zhengqian Li, Taotao Liu, Ning Yang, Dengyang Han, Xinning Mi, Yue Li, Kaixi Liu, Alain Vuylsteke, Hongbing Xiang, Xiangyang Guo. Neurological manifestations of patients with COVID-19: potential routes of SARS-CoV-2 neuroinvasion from the periphery to the brain[J]. Front. Med., 2020, 14(5): 533-541.
[5] Lingling Tang, Yingan Jiang, Mengfei Zhu, Lijun Chen, Xiaoyang Zhou, Chenliang Zhou, Peng Ye, Xiaobei Chen, Baohong Wang, Zhenyu Xu, Qiang Zhang, Xiaowei Xu, Hainv Gao, Xiaojun Wu, Dong Li, Wanli Jiang, Jingjing Qu, Charlie Xiang, Lanjuan Li. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19[J]. Front. Med., 2020, 14(5): 664-673.
[6] Jiuyang Xu, Yijun Chen, Hao Chen, Bin Cao. 2019 novel coronavirus outbreak: a quiz or final exam?[J]. Front. Med., 2020, 14(2): 225-228.
[7] Fanghua Gong, Yong Xiong, Jian Xiao, Li Lin, Xiaodong Liu, Dezhong Wang, Xiaokun Li. China’s local governments are combating COVID-19 with unprecedented responses ---- from a Wenzhou governance perspective[J]. Front. Med., 2020, 14(2): 220-224.
[8] Li Ni, Ling Zhou, Min Zhou, Jianping Zhao, Dao Wen Wang. Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19[J]. Front. Med., 2020, 14(2): 210-214.
[9] Wei Liu, Jing Wang, Wenbin Li, Zhaoxian Zhou, Siying Liu, Zhihui Rong. Clinical characteristics of 19 neonates born to mothers with COVID-19[J]. Front. Med., 2020, 14(2): 193-198.
[10] Sarah H. Alfaraj, Jaffar A. Al-Tawfiq, Talal A. Altuwaijri, Ziad A. Memish. Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia[J]. Front. Med., 2019, 13(1): 126-130.
[11] Yujia Jin, Cheng Lei, Dan Hu, Dimiter S. Dimitrov, Tianlei Ying. Human monoclonal antibodies as candidate therapeutics against emerging viruses[J]. Front. Med., 2017, 11(4): 462-470.
[12] Jaffar A. Al-Tawfiq, Ali S. Omrani, Ziad A. Memish. Middle East respiratory syndrome coronavirus: current situation and travel-associated concerns[J]. Front. Med., 2016, 10(2): 111-119.
[13] Mahmoud M. Shehata,Mokhtar R. Gomaa,Mohamed A. Ali,Ghazi Kayali. Middle East respiratory syndrome coronavirus: a comprehensive review[J]. Front. Med., 2016, 10(2): 120-136.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed