How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses?
Abstract
:1. Introduction
1.1. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of SARS-CoV Replication
Entry a/DRD Approach, Structure, and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
1.1/A | 6-azauridine | EC50 16.8 (2.9) mg/L; Vero; FFM-1 (FFM-2) CC50 104 (18) mg/L; Vero SI 6 | [30] | |
1.2/A | pyrazofurin | EC50 4.2 (0.57) mg/L; Vero; FFM-1 (FFM-2) CC50 52 (9.6) mg/L; Vero SI 12 | [30] | |
EC90 27 μM; Urbani IC90 32 μM; Vero E6 SI 1 | [31] | |||
1.3/A | R1 = H or DMTr R2 = H or OH R3 = H, OH, OMe R4 = H, Me, Br, Cl R5 = H, Bz, Ac (10 compounds) | R1,R2,R4,R5 = H, R3 = OMe: EC50 4 μM; Vero 76; Urbani IC50 23 μM; Vero 76 SI 6 | [31] | |
1.4/A | 3-deazaneplanocin A | EC50 > 380 μM; Vero E6; Urbani IC50 > 380 μM; Vero E6 | [31] | |
IC50 > 100 μM; Urbani CC50 > 100 μM; Vero 76 | [32] | |||
1.5/A | cidofovir | EC50 > 360 μM; Vero 76; Urbani IC50 > 360 μM; Vero 76 | [31] | |
1.6/A | R1, R2, R3 = H or OH R4 = OH or NH2 R5 = H or NH2 | 2′-deoxytubercidin (R1,R2 = OH, R3,R5 = H, R4 = NH2, X = CH): EC50 0.1 μM; Vero E6; Urbani IC50 0.4 μM; Vero E6 SI 4 | [31] | |
1.7/A | R1 = CN, CO2H R2 = OH, OAc, OBn, Br, P(O)(OEt)2 (5 compounds) | R1 = CN, R2 = OAc: IC50 15 μg/mL; Vero CC50 56 μg/mL; Vero | [33] | |
1.8/A | X, Y = CH2 or O (2 compounds) | X = CH2, Y = O: IC50 23 μg/mL; Vero CC50 > 75 μg/mL; Vero | [33] | |
1.9/A | R1 = Tol, H, Bz, Ac R2 = H, OH, OAc, OBz, R3 = CN, CO2Me, C(O)NHNH2, C(O)NH2 (7 compounds) | R1,R2 = H, R3 = CO2Me: IC50 18 μg/mL; Vero CC50 > 75 μg/mL; Vero | [33] | |
1.10/A | R1 = CN, CO2H CO2Me, R2 = OH, OAc, P(O)(OH)2 (4 compounds) | R1 = CO2Me, R2 = OH: IC50 28 μg/mL; Vero CC50 > 75 μg/mL; Vero | [33] | |
1.11/A | NHC | EC50 5 μM; Vero E6; Urbani IC50 50 μM; Vero E6 SI 10 | [31] | |
1.12/A | ribavirin | IC50 0.1 ± 0.0 μM; Vero; Urbani CC50 12.5 ± 3.5 μM; Vero 76 SI > 125 | [32] | |
IC50 from 50 to 100 μg/mL; fRhK4; ten clinical isolates CC50 > 1000 μg/mL; fRhK4 SI from 50 to >80 | [34] | |||
IC50 20 ± 15 μg/mL; Vero E6; Frankfurt-1 CC50 40 μg/mL; Vero E6 (2 virus variants evaluated) | [35] | |||
IC50 210 μM; Vero 76; Urbani CC50 283 μM; Vero 76 SI 1 | [16] | |||
IC50 0.14 μM; HAE; GFP | [36] | |||
1.13/A | mizoribine | IC50 3.5 ± 2.9 μg/mL; Vero E6; Frankfurt-1 CC50 > 200 μg/mL; Vero E6 (2 virus variants) | [35] | |
IC50 > 40 μM; Vero 76; Urbani CC50 > 40 μM; Vero 76 SI 0 e | [16] | |||
IC50 13.5 μM; Vero E6; Frankfurt-1 CC50 > 700 μM; Vero E6 SI > 52 | [37] | |||
1.14/A | EICAR | IC50 > 40 μM; Vero 76; Urbani CC50 > 40 μM; Vero 76 SI 0 | [16] | |
1.15/A | B = 5-chlorouracil-1-yl, thymin-1-yl, cytosin-1-yl, uracil-1-yl, adenin-1-yl | B = 5-chlorouracil-1-yl: EC50 < 10 μM; Vero 76 IC50 28 μM; Vero 76 SI > 2.8 | [38] | |
1.16/A | B = thymin-1-yl, cytosin-1-yl, adenin-1-yl or guanin-1-y | B = thymin-1-yl: EC50 10.3 μM; Vero 76 IC50 16.1 μM; Vero 76 SI 1.6 | [38] | |
1.17/A | B = thymin-1-yl, adenin-1-yl or guanin-1-yl | B = adenin-1-yl: EC50 11.1 μM; Vero 76 IC50 3.5 μM; Vero 76 SI 0 e | [38] | |
1.18/A | B = cytosin-1-yl, adenin-1-yl or thymin-1-yl | B = adenin-1-yl: EC50 11.1 μM; Vero 76 IC50 14.5 μM; Vero 76 SI 1.3 | [38] | |
1.19/A | B = adenin-1-yl, thymin-1-yl or cytosin-1-yl | B = adenin-1-yl: EC50 11.9 μM; Vero 76 IC50 25.6 μM; Vero 76 SI 2.2 | [38] | |
1.20/A | B = thymin-1-yl, uracil-1-yl, adenin-1-yl, inosin-1-yl or guanin-1-yl | B = thymin-1-yl: EC50 20 μM; Vero 76 IC50 > 100 μM; Vero 76 SI 5 | [38] | |
1.21/A | B = uracil-1-yl, cytosin-1-yl, adenin-1-yl, inosin-1-yl or guanin-1-yl | B = cytosin-1-yl: EC50 20 μM; Vero 76 IC50 20 μM; Vero 76 SI 1 | [38] | |
1.22/A | dioxolane T (DOT) | EC50 24.5 μM; Vero 76 IC50 > 100 μM; Vero 76 SI 4.1 | [38] | |
1.23/A | EC50 28.6 μM; Vero 76 IC50 > 18.8 μM; Vero 76 SI 0 | [38] | ||
1.24/A | EC50 76.8 μM; Vero 76 IC50 > 100 μM; Vero 76 SI 1.3 | [38] | ||
1.25/A | B = thymin-1-yl, N-OH-cytosin-1-yl, adenin-1-yl (neplanocin A) or inosin-1-yl | EC50 > 100 μM; Vero 76 IC50 > 10 μM; Vero 76 SI 0 | [38] | |
1.26/A | B = thymin-1-yl or inosin-1-yl | EC50 > 100 μM; Vero 76 IC50 > 100 μM; Vero 76 SI 0 | [38] | |
1.27/A | R = OMe or SMe | IC50 > 300 μM; Vero E6; Frankfurt-1 | [37] | |
1.28/A | gemcitabine | EC50 4.957 μM; Vero E6 | [39] | |
1.29/A e | galidesivir (BCX4430, immucillin-A) | EC50 57.7 μM; Urbani CC50 > 296 μM; Vero 76 SI > 5.1 | [40] | |
1.30/A | acyclovir | EC50 > 1000 μM; Vero E6; Frankfurt-1 CC50 > 1000 μM; Vero E6 | [41] | |
1.31/A | remdesivir | IC50 0.069 ± 0.036 μM CC50 > 10 μM; HAE SI > 100 | [42,43] | |
1.32/A | AT-511 (bemnifosbuvir, free form of AT-527) | EC90 0.34 μM CC50 > 86 μM; Huh7 SI > 250 | [44] | |
1.33/D | X, Y = CH or N(3 compounds) | X = CH, Y = N: EC50 21 μM IC50 > 100 μM SI > 4.8 | [45] | |
1.34/D | R = H or Bz X---X = CH-CH or X = CH2 (4 compounds) | R = Bz, X---X = CH-CH: IC50 14.5 μM; Frankfurt-1 CC50 78 μM; Vero E6 SI 5.4 | [37] | |
1.35/D | R1 = H or Bz R2, R3 = H or OH R4 = H or NH2 (5 compounds) | R1,R2, R3 = OH, R4 = H: IC50 48.7 μM; Vero E6; Frankfurt-1 CC50 279 μM; Vero E6 SI 5.7 | [37] | |
1.36/D | R = Me, vinyl, ethynyl | R = vinyl: EC50 14.0 μM; Vero; Toronto-2 CC50 > 30 μM; Vero | [46] | |
1.37/D | GS-441524 | IC50 0.18 ± 0.14 μM; HAE CC50 > 100 μM; HAE | [42,43] | |
EC50 2.4 μM; Vero; Toronto-2 CC50 > 30 μM; Vero | [46] | |||
1.38/D e | X, Y = H or F B = uracil-1-yl, cytosin-1-yl N6-Me-adenin-1-yl, adenin-1-yl, R = H or (12 compounds) | X,Y = F, B = adenin-1-yl, R = H: EC50 0.5 μM; Vero E6; Frankfurt 1 CC50 5.9 μM; Vero E6 SI 11.8 | [47] |
1.2. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of SARS-CoV-2 Replication
Entry a/DRD Approach, Structure and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
2.1/A | NHC | IC50 0.08 μM; Calu-3 | [36] | |
EC50 0.3 ± 0.2 μM; Vero CC5012.6 μM; Vero SI 42 | [52] | |||
2.2/A | GS-441524 | EC50 8.2 ± 0.4 μM; Vero CC50 > 100 μM; Vero SI 12 | [52] | |
EC50 0.59 ± 0.10 μM); Vero E6 CC50 > 500 μM; Vero E6 SI > 847.46 (2 virus variants evaluated) | [53] | |||
EC50 0.10 μM; Calu-3; WA1 CC50 > 50 μM; Calu-3 SI > 524 | [54] | |||
2.3/A | remdesivir | EC50 1.0 ± 0.1 μM; Vero CC50 > 100 μM; Vero SI > 100 | [52] | |
2.4/A | R1 = Me, Cl, Br R2, R3 = or R2 = H and R3 = (4 compounds) | R1 = Me, R2, R3 = : EC50 6.3 ± 0.1 μM; Vero CC50 16.4 μM; Vero | [52] | |
2.5/A | EC50 7.6 ± 0.4 μM; Vero CC50 > 100 μM; Vero SI > 10 | [52] | ||
2.6/A | 2′-MeC: R1 = H, R2 = OH, R3 = Me ALS-8112: R1 = CH2Cl, R2 = F, R3 = H | 2′-MeC: EC50 9.2 ± 0.1 μM; Vero CC50 > 100 μM; Vero SI > 10 | [52] | |
2.7/A | entecavir | EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
2.8/A | lamivudine: R = H emtricitabine: R = F | lamivudine and emtricitabine EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
2.9/A | tenofovir alafenamide: R = tenofovir isoproxil: R = | tenofovir alafenamide and tenofovir isoproxil: EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
2.10/A d | tubercidin | EC50 0.77 μM; Vero E6 CC50 > 100 μM; Vero E6 SI 129.87 | [55] | |
EC90 0.087 μM; Caco-2; WK-521 CC50 0.66 μM; MRC5 | [56] | |||
EC50 0.05 μM; Calu-3; WA1 CC50 9.36 μM; Calu-3 SI 190 | [54] | |||
2.11/A | penciclovir | EC50 95.96 μM; Vero E6 CC50 > 400 μM; Vero E6 SI 4.17 | [55] | |
2.12/A | AT-511 (bemnifosbuvir, free form of AT-527) | EC90 0.47 ± 0.12 μM; HAE CC50 > 86 μM; HAE SI > 160 | [44] | |
2.13/A e | galidesivir (BCX4430, immucillin-A) | EC50 14.15 μM; Calu-3; WA1/2020 CC50 > 50 μM; Calu-3 SI > 3.5 | [50] | |
2.14/A e | 5-hydroxymethyltubercidin | EC90 0.57 μM; Caco-2; WK-521 CC50 > 50 μM; MRC5 | [56] | |
2.15/A e | R1 = H or CN R2 = H, CH=NOH, NO2 Me, CN (5 compounds) | R1 = H, R2 = CH=NOH: EC90 0.20 μM; Caco-2; WK-521 CC50 0.74 μM; MRC5 | [56] | |
2.16/A e | EC90 3.5 μM Caco-2; WK-521 CC50 24 μM; MRC5 | [56] | ||
2.17/A | R = H or | Sofosbuvir, R = : EC50 5.1 ± 0.8 μM, Huh-7; clinic isolate CC50 381 ± 34 μM, Huh-7 SI 74 | [57] | |
2.18/A | thioguanosine | EC50 0.04 μM; Calu-3; WA1 CC50 1.14 μM; Calu-3 SI 26 | [54] | |
IC50 0.78 µM, Caco-2; clinic isolate | [58] | |||
2.19/A | gemcitabine | EC50 0.04 μM; Calu-3; WA1 CC50 > 20 μM; Calu-3 SI > 1235 | [54] | |
2.20/A | R1 = H or OH R2 = H or NH2 (2 compounds) | 6-thioinosine (R1 = OH, R2 = H): EC50 0.05 μM; Calu-3; WA1 CC50 > 50 μM; Calu-3 SI > 1083 | [54] | |
2.21/A | 3-deazaneplanocin A | IC50 579 nM; SARS-CoV-2; A549-nRFP-ACE2; SARS-CoV-2-MUC-IMB-1 (in combination with remdesivir) | [59] | |
2.22/A e | sangivamycin | EC50 15.4 nM; Vero E6; B.1.1.7 (Alpha) SI 39.0 (8 virus variants evaluated) | [60] | |
2.23/A e | cordycepin | EC50 2.01 ± 0.12 μM; Vero E6; VOC-202012/01 CC50 > 100 μM; Vero E6 | [61] | |
2.24/A e | didanosine | EC50 3.10 ± μM; Vero E6; VOC-2020/01 CC50 > 100 μM; Vero E6 | [62] | |
2.25/A e | riboprine: R = 3-methylbut-2-en-1-yl tecadenoson: R = (R)-tetrahydrofuran-3-yl | riboprine: EC50 408 ± 22 nM; Vero E6; Omicron B.1.1.529/BA.5; CC50 > 100 μM; Vero E6 (3 virus variants evaluated) | [63,64,65,66] | |
2.26/A e | forodesine | EC50 657 ± 34 nM; Vero E6; Omicron B.1.1.529/BA.5 CC50 > 100 μM; Vero E6 (3 virus variants evaluated) | [63,64,65,66] | |
2.27/A e | maribavir | EC50 3000 ± 131 nM; Vero E6; Omicron B.1.1.529/BA.5 CC50 > 100 μM; Vero E6 (3 virus variants evaluated) | [63,64,65] | |
2.28/A | nelarabine: R1 = OMe, R2 = NH2vidarabine: R1 = NH2, R2 = H | nelarabine: EC50 1656 ± 71 nM; Vero E6; Omicron B.1.1.529/BA.5 CC50 > 100 μM; Vero E6 (3 virus variants evaluated) | [63,64,65] | |
2.29/A | 5-azacytidine | EC50 2.63 μM; Calu-3; Wuhan/WIV0 4/2019 CC50 25.40 μM; Calu-3 SI 9.66 | [67] | |
2.30/A/B e | azvudine: R = H CL-236: R = | CL-236: EC50 1.2 μM; Calu-3; BetaCoV/Wuhan/WIV04/2019 CC50 > 102.4 μM; Calu-3 SI 83 | [68,69,70] | |
2.31/A/D e | R1 = H, R2 = furan-2-yl: EC50 0.1 ± 0.03 μM; Huh7; hCoV-19/Czech Republic/NRL_6632_2/2020 CC50 11 ± 2.5 μM; Huh7 | [71] | ||
R2 = Me, vinyl, ethynyl, cyclopropyl, furan-2-yl, thiophen-2-yl, Ph, benzofuran-2-yl, benzothiophen-2-yl, naphtalen-2-yl R2 = H, (proTide), (bis(SATE), (mono(SATE) (25 compounds) | ||||
2.32/B | molnupiravir | EC50 0.10 μM; Calu-3; WA1 CC50 > 50 μM; Calu-3 SI > 500 | [36,54] | |
2.33/B e | R = 4-oxaicosan-1-yl, 3-oxahenicosan-1-yl, 2-OBn-4-oxadocosan-1-yl | R = 2-OBn-4-oxadocosan-1-yl: EC50 0.14 μM; Vero E6; USA-WA1/2020 CC50 97.9 μM; Vero E6 SI 699 | [72,73] | |
2.34/B e | R1 = alkyl, cycloalkyl, CF3CH2, C6H5, α-aminoalkyl R2, R3, R4 = H, acetyl, isobutyryl (21 compounds) | obeldesivir (ATV006, R1 = isopropyl; R2,R3,R4 = H): EC50 0.106 μM; Vero E6; Omicron, B.1.1.529 CC50 128.00 μM; Vero E6 SI 1207.55 (4 virus variants evaluated) | [74] | |
2.35/B | X = O or CH2 R1 = OH or F R2 = C10H21, C12H23, C14H29 (5 compounds) | X = CH2, R = C14H29: EC50 0.31 μM; Vero; B1.1 529 BA.1 (Omicron); CC50 6.32 μM; Vero (5 virus variants evaluated) | [75] | |
2.36/C | EC50 3.30 μM; Vero E6 (2 virus strains evaluated) | [53] | ||
2.37/C e | R1,R2,R3 = H or isobutyryl (4 compounds) | VV116 (R1,R2,R3 = isobutyryl; hydrobromide): EC50 0.35 ± 0.09 µM; Vero E6 CC50 289.19 ± 15.39 μM; Vero E6 (2 virus variants evaluated) | [53] | |
2.38/C | EC50 29.91 μM; Vero; B1.1 529 BA.1 (Omicron); CC50 > 100 μM; Vero (5 virus variants evaluated) | [75] | ||
2.39/D | EC50~2 μM; Calu-3 CC50 > 25 μM; Calu-3 SI > 12 μM | [47] | ||
2.40/D | B = thymin-1-yl, uracil-1-yl, N6-DMTr-adenin-1-yl R1 = TBDMS or (iPr)2Si-O-Si(iPr)2 R2 = C4H9, Ac, pyranos-1-yl (11 compounds) | B = thymin-1-yl, R1 = (iPr)2Si-O-Si(iPr)2, araR2 = C4H9: EC50 17 μM; Vero E6; MOI 0.05 CC50 16.6 μM; Vero E6 | [76] |
1.3. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of MERS-CoV Replication
Entry a/DRD Approach, Structure, and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
3.1/A | ribavirin | IC50 9.99 ± 2.97 μg/mL; Vero CC50 > 1660 μg/mL; Vero SI > 152.98 | [81] | |
3.2/A e | galidesivir (BCX4430, immucillin-A) | EC50 68.4 μM; Vero E6; Jordan N3 CC50 > 100 μM; Vero E6 SI > 1.5 | [40] | |
3.3/A | R1 = H, Me R2 = NH2 (3 compounds) | R1 = Me, R2 = NH2: EC50 23 ± 0.6 μM; Vero; EMC/2012 CC50 71 ± 14 μM; Vero | [41] | |
3.4/A | acyclovir | EC50 > 1000 μM; Vero; EMC/2012 CC50 > 1000 μM; Vero | [41] | |
3.5/A | remdesivir | EC50 0.34 μM; Vero CC50 > 20 μM; Vero | [82] | |
IC50 0.025 μM; Calu-3 CC50 > 10 μM; Calu-3 SI > 400 | [42] | |||
IC50 0.074 ± 0.023 μM; HAE CC50 > 10 μM; HAE SI > 100 | [42,43] | |||
3.6/A | GS-441524 | IC50 0.86 ± 0.78 μM; HAE CC50 > 100 μM; HAE | [42,43] | |
3.7/A | NHC | IC50 0.56 μM; DBT-9 CC50 > 200 µM; DBT-9 | [83] | |
IC50 0.024 μM; HAE; RFP (2 virus variants evaluated) | [36] | |||
3.8/A | gemcitabine | EC50 1.216 μM; Vero E6 | [39] | |
3.9/A | AT-511 (bemnifosbuvir, free form of AT-527) | EC90 37 ± 28μM; Huh7 CC50 > 86 μM; Huh7 SI > 3.3 | [44] | |
3.10/D | X = H or F Y = H or F B = uracil-1-yl, cytosin-1-yl, adenin-1-yl, N6-Me-adenin-1-yl, R = H or (14 compounds) | X,Y = F, B = adenin-1-yl, R = H: EC50 0.2 μM; Vero E6; EMC/2012 CC50 3.2 μM; Vero E6 SI 16 | [47,51] |
1.4. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of HCoV-OC43 Replication
Entry a/DRD Approach, Structure, and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
4.1/A | remdesivir | EC50 0.04 ± 0.1 μM Huh7 CC50 2.1 μM; Huh7 SI 52 | [52] | |
4.2/A | NHC | EC50 0.8 ± 0.03 μM; Huh7 CC50 80.3 μM; Huh7 SI 100 | [52] | |
4.3/A | R1 = Me, Cl, Br R2, R3 = or R2 = H and R3 = (4 compounds) | R2 = H, R1 = Cl, R3 = : EC50 5.9 ± 0.6 μM; Huh7 CC50 > 100 μM; Huh7 | [52] | |
4.4/A | EC50 6.7 ± 1.1 μM; Huh7 CC50 38 μM; Huh7 | [52] | ||
4.5/A | 2′-MeC: R1 = H, R2 = OH, R3 = Me ALS-8112: R1 = CH2Cl, R2 = F, R3 = H | 2′-MeC: EC50 10 ± 0.7 μM; Huh7 CC50 > 100 μM; Huh7 | [52] | |
4.6/A | entecavir | EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
4.7/A | GS-441524 | EC50 > 10 μM; Vero CC50 13.2 ± 0.8 μM; Vero | [52] | |
4.8/A | lamivudine: R = H emtricitabine: R = F | Lamivudine and emtricitabine: EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
4.9/A | tenofovir alafenamide: R = tenofovir isoproxil: R = | EC50 > 20 μM; Vero CC50 > 20 μM; Vero | [52] | |
4.10/A | ribavirin | EC50 20.6 μM; Huh7 CC50 22.1 μM; Huh7 | [52] | |
4.11/A | AT-511 (bemnifosbuvir, free form of AT-527) | EC90 0.5 μM; Huh7 CC50 > 86 μM; Huh7 SI > 170 (2 virus variants evaluated) | [44] | |
4.12/A | tubercidin | EC50 0.11 μM; MRC5 CC50 0.66 μM; MRC5 | [56] | |
4.13/A | 5-hydroxymethyltubercidin | EC50 0.378 ± 0.023 μM; MRC5 CC50 > 50 μM; MRC5 SI > 132 | [56] | |
4.14/A | R1 = H or CN R2 = H, CH=NOH, NO2 Me, CN (5 compounds) | R1 = H, R2 = CH=NOH: EC90 0.055μM; MRC5 CC50 0.74 μM; MRC5 | [56] | |
4.15/B | CL-236 | EC50 1.2 μM; H460; VR1558 SI 20 | [68] |
1.5. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of HCoV-229E Replication
Entry a/DRD Approach, Structure, and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
5.1/A e | remdesivir | EC50 0.07 μM; MRC5 TC50 > 2.0 μM; MRC5 SI > 28.6 | [84] | |
5.2/A | R = H (alovudine) or CH3CH2S(CH2)11C(O)– | R = CH3CH2S(CH2)11C(O)–: EC50 > 45.4 μM; MRC5 TC50 45.4 μM; MRC5 | [84] | |
5.3/A | R = H (lamivudine) or CH3(CH2)12C(O)– | R = CH3(CH2)12C(O)–: EC50 > 47.5 μM; MRC5 TC50 47.5 μM; MRC5 | [84] | |
5.4/A | islatravir | EC50 > 55.3 μM; MRC5 TC50 55.3 μM; MRC5 | [84] | |
5.5/A | R = H (emtricitabine) or CH3(CH2)12C(O)– | R = CH3(CH2)12C(O)–: EC50 87.5 μM; MRC5 TC50 72.8 μM; MRC5 SI 1.2 | [84] | |
5.6/A | tenofovir | EC50 > 100 μM; MRC5 TC50 > 100 μM; MRC5 | [84] | |
5.7/A | AT-511 (bemnifosbuvir, free form of AT-527) | EC50 1.8 ± 0.3 μM; BHK-21 CC50 > 100 μM; BHK-21 SI > 55 (2 virus variants evaluated) | [44] | |
5.8/A | tubercidin | EC50 < 0.078 μM; MRC5 CC50 0.66 μM; MRC5 | [56] | |
5.9/A | 5-hydroxymethyltubercidin | EC50 0.528 ± 0.029 μM; MRC5 CC50 > 50 μM; MRC5 SI > 94 | [56] | |
5.10/A | R1 = H or CN R2 = H, CH=NOH, NO2 Me, CN(5 compounds) | R1 = H, R2 = CH=NOH: EC90 < 0.078 μM; MRC5 CC50 0.74 μM; MRC5 | [56] | |
5.11/A | EC50 4.0 μM; HEL CC50 10 μM; HEL | [76] | ||
5.12/B | R = 4-oxaicosan-1-yl, 3-oxahenicosan-1-yl, 2-OBn-4-oxadocosan-1-yl | R = 2-OBn-4-oxadocosan-1-yl: EC50 0.15 μM; MRC5 CC50 > 50 μM; MRC5 | [72] | |
5.13/D | R = H or F | R = H: EC50 18.5 ± 13.5 μM; HEL MCC > 20 μM; HEL | [85] | |
5.14/D | B = thymin-1-yl, uracil-1-yl, N6-DMTr-adenin-1-yl R1 = TBDMS or (iPr)2Si-O-Si(iPr)2R2 = C4H9, Ac, pyranos-1-yl (11 compounds) | B = uracil-1-yl, R1 = (iPr)2Si-O-Si(iPr)2, araR2 = C4H9: EC50 4.1 μM; HEL CC50 10 μM; HEL | [76] |
1.6. The Nucleoside Analogs Evaluated as In Vitro Inhibitors of HCoV-NL63 Replication
Entry a/DRD Approach, Structure, and Number of Compounds Examined | Effective Concentration Value b; Cell Line; Virus Variant (If Given) Cytotoxic Concentration Value c; Cell Line Selectivity Index d (SI, If Given) | Ref. | ||
---|---|---|---|---|
6.1/A | R1 = H, Me R2 = NH2 (3 compounds) | R1 = Me, R2 = NH2: EC50 8.8 ± 1.5 μM; Vero 118; clinic isolate CC50 120 ± 37 μM; Vero 118 | [41] | |
6.2/A | acyclovir | EC50 > 100 μM; Vero 118; clinic isolate CC50 > 100 μM; Vero 118 | [41] | |
6.3/A | 6-azauridine | IC50 32 nM; LLC-MK2; Amsterdam 1 CC50 80 μM; LLC-MK2 SI 2500 | [86] | |
6.4/A | NHC | IC50 400 nM; LLC-MK2; Amsterdam 1 CC50 > 100 μM; LLC-MK2 SI > 250 | [86] |
1.7. The Nucleoside Analogs Evaluated as Inhibitors of HCoV-Related Enzymes
Entry a/DRD Approach, Structure and Number of Compounds Examined | Object of Study b Antiviral Effect(s) If Given c | Ref. | ||
---|---|---|---|---|
7.1/A | X = S or (S)-CH-NH2 n = 1 or 2 (3 compounds) | Inhibition of SARS-CoV nsp14 and SARS-CoV nsp16–nsp10 complex sinefungin (X = (S)-CH-NH2, n = 2): IC50 496 nM ± 18, nsp14 IC50 736 nM ± 71; nsp16/nsp10 AdoHcy (X = S, n = 2): IC50 16 µM ± 1.2, nsp14 IC50 12 µM ± 1.9, nsp16/nsp10 | [87,88] | |
X = N or N+–Me Y = N or CH R1 = OH, SMe, SiBu, –O[P(O)(OH)O]3H R2 = H or Ac R3 = H or NH2 (6 compounds) | ||||
X = N or C-C≡CH R = H or –[P(O)(OH)O]3H (3 compounds) | ||||
7.2/A | X = S (AdoHcy) or (S)-CH-NH2 (sinefungin) | Inhibition of MERS-CoV nsp16–nsp10 complex AdoHcy: IC50 7 µM ± 0.4 sinefungin: IC50 7.4 μM ± 0.9 | [88,89] | |
7.3/A | R1 = H, OH, Me, F R2 = H, OH, Me B = cytosin-1-yl, uracil-1-yl, adenin-9-yl, 3-carbamoyl-5-fluoro-2-oxopyrazin-1-yl, 3-carbamoyl-1H-1,2,4-triazol-1-yl (7 compounds) | Selectivity of the SARS-CoV-2 RdRp towards incorporation of the nucleoside analog triphosphate into viral RNA over a natural nucleotide. Low discrimination of the enzyme against the cytidine triphosphate derivative (B = cytosin-1-yl, R1 = F, R2 = H) over the reference cytidine triphosphate | [89,90] | |
7.4/A | R1 = OH, N3, F R2 = H or F R3 = H or Me R4 = H or Me (3 compounds) | Proclivity of SARS-CoV RdRp or SARS-CoV-2 RdRp to incorporate the nucleoside triphosphate into the virus RNA Sofosbuvir nucleoside triphosphate (R1 = OH, R2 = F, R3 = Me, R4 = H) was incorporated by the RdRp, terminated the polymerase reaction and was resistant to SARS-CoV-2 proofreader | [90,91,92,93] | |
triphosphate of lamivudine (R = H) or emtricitabine (R = F) | ||||
carbovir triphosphate | ||||
7.5/A | GS-441524 triphosphate | Incorporation of nucleotide analogs to viral RNA by SARS-CoV-2 RdRp The incorporation of GS-441524 triphosphate and delay in viral RNA chain termination | [93,94] | |
R1 = F, OH, NH2, H, OMe R2 = F, H, Me, OH, N3 B = cytosin-1-yl, uracil-1-yl, purin-9-yl (6-Cl-; 6-NH2,2-Cl; 6-SMe,2-NH2; 6-SH,2- NH2), guanin-9-yl, 8-oksoguanin-9-yl, 3-carbamoyl-1H-1,2,4-triazol-1-yl, 3-carbamoyl-5-fluoro-2-oxopyrazin-1-yl (15 compounds) | ||||
lamivudine triphosphate | ||||
stavudine triphosphate | ||||
tenofovir triphosphate | ||||
7.6/A d | X = N or C-CN Y = S, (S)-CHCH2NH2, N-CH2CH2C6H4-C(O)NH2-3 (4 compounds) | Inhibition of SARS-CoV-2 nsp14, SARS-CoV-2 nsp10–nsp16 complex from SARS-CoV, SARS-CoV-2, HCoV-OC43, HCoV-HKU1, HCoV-NL63, HCoV-229E, and MERS-CoV and selectivity against 20 human protein lysine methyltransferases Compound SS148 (X = C-CN, Y = S): IC50 0.07 ± 0.006 µM; SARS-CoV-2 nsp14 IC50 0.2 ± 0.04 µM; HCoV-NL63 nsp10–nsp16 complex Compound WZ16 (X = N, Y = (S)-CH-CH2NH2): IC50 0.19 ± 0.04 µM; SARS-CoV-2 nsp14 IC50 2.5 ± 0.1 µM; SARS-CoV nsp10–nsp16 complex | [94,95,96] | |
R = -CH2-CH2-C6H5 (DS0464) or -CH2-c-C6H11 | ||||
7.7/A d | thioguanosine | The inhibitory effect on SARS-CoV-2 3CL-Pro IC50 6.3 μM; SARS-CoV-2 3CL-Pro IC50 3.9 μM; SARS-CoV-2; Vero E6 CC50 > 20, Vero E6 | [97] | |
7.8/A d | EIDD-2749 | Inhibition of SARS-CoV-2 RdRp EC50 2.47 μM; HAE; USA-WA1/2020 CC50 467.9 μM; HAE | [98] | |
7.9/A d | R1 = H or –[P(O)(OH)O]3H R2,R3 = H or OH R4 = SH or NH2 R5 = NH2, F or H X = N or C-I (4 compounds) | Inhibition of SARS-CoV-2 RdRp R1,R3,R5 = H, R2 = OH, R4 = NH2, X = C-I EC50 0.75 μM; SARS-CoV-2 RdRp CC50 59.46 μM; HEK 293T EC50 1.56 μM; HCoV-OC43; HCT-8 EC50 3.62 μM; HCoV-NL63; LLCM-K2 | [99] | |
7.10/A d | sinefungin | Disruption of WT SARS-CoV-2 nsp16 activity | [100] | |
7.11/D d | R = H, (S)-3-NH2-4-CO2H-prop-1-yl, alkyl, substituted benzyl or benzenesulfonyl (16 compounds) | Inhibition of SARS-CoV nsp14 R = –S(O)2-C6H3-3-NO2,4-Cl: IC50 0.6 ± 0.1 µM | [101] | |
7.12/D d | Ar = Ph, naphtyl, guinolin-3-yl, benzimidazol-2-yl, benzo[b]thiophen-5-yl X = CH2, –CH2–CH2–, –C≡C– (8 compounds) | Inhibition of SARS-CoV nsp14 R = guinolin-3-yl: IC50 3 ± 0.5 nM | [102] | |
7.13/D d | X = CH2 or C(O) Y = S, NH, N(3°), 1,2,3-triazole, piperazine R = substituted alkyl, aryl, benzyl (36 compounds) | Inhibition of SARS-CoV-2 nsp14, SARS-CoV-2 nsp16–nsp10 complex or hGNMT X = CH2, Y = S, R = CH2-C6H3-3-CO2H,5-Ph: IC50 0.58 ± 0.03 nM; nsp14 X = CH2 Y = S, R = CH2-C6H3-3-CO2H: IC50 4 ± 0.5 nM; nsp16/nsp10 | [103,104] | |
7.14/D d | X = S(O)2, C(O) R1 = substituted phenyl R2 = H, Et, alkyl (39 compounds) | Inhibition of SARS-CoV-2 nsp14 X = S(O)2, R1 = C6H3-3-CN,4-OMe, R2 = Et: IC50 0.019 µM | [105] | |
7.15/D | R = NO2, NH2, CF3, Me, Cl, NHAc n = 1 or 2 (20 compounds) | Inhibition of SARS-CoV-2 nsp14 R = 4-NO2, n = 1: 40% inhibition of SARS-CoV-2 nsp14 at the compound concentration of 5 µM | [106] | |
7.16/D d | R2 = H, Ac, isobutyryl R3 = H or Ac X = CH2, C(O), S(O)2 Y = N or CH Z = C or N R1 = napht-2-yl, quinolin-7-yl, 2-Cl-quinolin-6-yl (11 compounds) | Inhibition of SARS-CoV-2 nsp14 X = S(O)2, Y = CH, Z = N, R1 = napht-2-yl, R2 = H, R3 = H: IC50 0.093 µM; nsp14 EC50 0.72 µM; SARS-CoV-2; A459 AT CC50 > 100 µM; A459 AT | [107] | |
7.17/D d | R1 = Br, Me, OMe; R2 = Cl, NO2, CN; R3 = H, Me, Et; X = OH or NHMe; Y = Ph or quinolin-3-yl (26 compounds) | Inhibition of SARS-CoV nsp14, SARS-CoV-2 nsp14, MERS-CoV nsp14 R1 = OMe, R2 = CN, R3 = Me, Y = quinolin-3-yl: IC50 0.141 ± 0.02 nM; SARS-CoV nsp14 IC50 0.72 ± 0.4 nM; SARS-CoV-2 nsp14 R1 = OMe, R2 = CN, R3 = Me, Y = Ph: IC50 1.25 ± 0.25 nM; MERS-CoV nsp14 | [108] |
2. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
3CL-Pro | 3C-like protease |
A459 cells | adenocarcinomic human alveolar basal epithelial cells |
ATP | adenosine triphosphate |
BHK-21 cells | baby hamster kidney fibroblast cells |
Calu-3 cells | human lung cells |
Caco-2 cells | human colorectal adenocarcinoma cells |
CC50 | 50% cytotoxic concentration |
DBT-9 cells | delayed brain tumor, murine astrocytoma clone 9 |
DMTr | dimethoxytrityl |
EC50 | 50% effective concentration |
fRhK4 cells | fetal rhesus monkey kidney cells |
H460 cells | human nonsmall cell lung cancer cells |
HAE cells | human tracheobronchial epithelial cells |
HCT-8 cells | human ileocecal adenocarcinoma cells |
HEK 293T cells | human embryonic kidney cells |
HEL cells | human embryonic lung cells |
Huh7 cells | well differentiated hepatocyte-derived carcinoma cells |
HSV-1 | herpes simplex virus 1 |
HSV-2 | herpes simplex virus 2 |
IC50 | 50% cytotoxic concentration |
IFN-I | Interferon type I |
KD | protein–ligand dissociation constant |
LLC-MK2 cells | rhesus monkey kidney epithelial cells |
MCC cells | Merkel cell carcinoma |
MRC-5 cells | human fetal lung fibroblast cells |
nsp14 | RNA cap guanine-N7-methyltransferase |
nsp16–nsp10 | 2′-O-methyltransferase nsp16–nsp10 complex |
RD cells | rhabdomyosarcoma cells |
RdRp | RNA-dependent RNA polymerase |
SAH | S-adenosyl-L-homocysteine |
SAM | S-adenosyl-L-methionine |
SCC-VII | squamous cell carcinoma |
TBDMS | tert-butyldimethylsilyl |
TC50 | 50% toxic concentration |
TP | –[P(O)(OH)O]3H |
Vero cells | Green Monkey kidney epithelial cells |
Vero 118 cells | Vero cells clone 118 |
Vero 76 cells | Vero cells clone 76 |
Vero E6 cells | Vero cells clone E6 |
Vero E6 TMPRSS2 cells | human transmembrane serine protease 2-expressing Vero E6 cells |
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Buchowicz, W.; Koszytkowska-Stawińska, M. How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses? Organics 2024, 5, 71-110. https://doi.org/10.3390/org5020006
Buchowicz W, Koszytkowska-Stawińska M. How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses? Organics. 2024; 5(2):71-110. https://doi.org/10.3390/org5020006
Chicago/Turabian StyleBuchowicz, Włodzimierz, and Mariola Koszytkowska-Stawińska. 2024. "How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses?" Organics 5, no. 2: 71-110. https://doi.org/10.3390/org5020006