Compounds and methods for treatment and prevention of flavivirus infection

Abstract

The present invention concerns the use of compounds for the treatment or prevention of Flavivirus infections, such as Zika virus infections. Aspects of the invention include methods for treating or preventing Flavivirus virus infection, such as Zika virus infection, by administering a compound or class of compound disclosed herein, such as a niclosamide compound, an emricasan compound, a cyclin-dependent kinase inhibitor, a proteasome inhibitor, or a combination of two or more of the foregoing, to a subject in need thereof; methods for inhibiting Flavivirus infections such as Zika virus infections in a cell in vitro or in vivo; pharmaceutical compositions; packaged dosage formulations; and kits for treating or preventing Flavivirus infections, such Zika virus infections.

We claim: 
     
         1 . A method for treating or preventing Flavivirus infection in a human or non-human animal subject, said method comprising administering an effective amount of at least one compound to a subject in need thereof, wherein the at least one compound inhibits Flavirus infection or suppresses Flavivirus-induced caspase-3 activity, and wherein the at least one compound comprises:
 (a) a niclosamide compound, or   (b) an emricasan compound, or   (c) a cyclin-dependent kinase (CDK) inhibitor, or   (d) a proteasome inhibitor, or   (e) a compound selected from among Teriflunomide, Hydroxocobalamin, Ensulizole, Tenonitrozole, Isoliquiritigenin, Nitazoxanide, Febuxostat, Leflunomide, Vidofludimus, SB-366791, Emodin, Diphenyl isophthalate, Benzoylpas, Fenobam, Indobufen, 2-(2H-Benzotriazol-2-yl)-4-methylphenol, Tiaprofenic acid, Flufenamic acid, Vitamin B12, Cinanserin, 5-Nitro-2-(3-phenylpropylamino)benzoic acid, Veliflapon, Thiabendazole, SIB 1893, Anethole trithione, Naringenin, Phenazopyridine, Fanetizole, Terazosin, Diacerein, CAY10505, Hesperetin, Suprofen, Ketorolac tromethamine, Piperine, Pirarubicin, Piraxostat, Albendazole oxide, Tyrphostin AG 494, Genistin, Fenbufen, Apatinib, RITA, BF-170 hydrochloride, OSI-930, Tribromsalan, Pifexole, Formononetin, Ebselen, Tranilast, Benzylparaben, 2-Ethoxylethyl-p-methoxycinnamate, Baicalein, Nemorubicin, Rutaecarpine, 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 5,7-Dihydroxyflavone, Vitamin B12, Pipofezine, Flurbiprofen axetil, 2-Amino-6-nitrobenzothiazole, Malachite green oxalate, Enfenamic acid, Fenaminosulf, AS-252424, Phenserine, Epalrestat, Alizarin, Dalcetrapib, SN-38, Echinomycin, (S)-(+)-Camptothecin, BI-2536, 10-hydroxycamptothecin, Topotecan, Delanzomib, Volasertib, Ispinesib, Paclitaxel, FK-506, Emetine, AVN-944, Digoxin, Vincristine, Idarubicin, Thapsigargin, Lexibulin, Ixazomib, Cephalomannine, Mitoxantrone, MLN-2238, Demecolcine, Vinorelbine, Bardoxolone methyl, Cycloheximide, Actinomycin D, AZD-7762, PF-184, CHIR-124, Cyanein, Triptolide, KX-01, PF-477736, Epirubicin, Mycophenolate (mycophenolic acid), Daunorubicin, PIK-75, Vindesine, Torin-2, Floxuridine, Go-6976, OSU-03012, or a prodrug, metabolite, or derivative of any of the foregoing, or   
       a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         2 . The method of  claim 1 , wherein the at least one compound comprises a combination of two or more of the compounds. 
     
     
         3 . The method of  claim 1 , wherein the Flavivirus infection is Zika virus infection. 
     
     
         4 . The method of  claim 1 , wherein the at least one compound comprises a compound in Table 7, or a prodrug, metabolite, or derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         5 . The method of  claim 1 , wherein the at least one compound comprises the niclosamide compound, and the niclosamide compound comprises:
 (a) niclosamide,   (b) a niclosamide derivative,   (c) a prodrug or metabolite of (a) or (b), or   (d) a pharmaceutically acceptable salt of (a), (b), or (c).   
     
     
         6 . The method of  claim 5 , wherein the niclosamide or niclosamide derivative has the structure of Formula 1: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6  are independently selected from the group consisting of a H; F; Cl; Br; I; OH; ketone (═O); (C 1-6 )alkyl; (C 2-6 )alkenyl; (C 2-6 )alkynyl; ether [—OR, where R can include (C 1-6 )alkyl; aralkyl; alkaryl; halogenated alkyl; heteroalkyl; aryl; heterocyclyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxyalkyl; aminoalkyl; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; acylamino; hydroxyl; alkoxy; alkoxyalkyl; aryloxy; arylalkoxy; acyloxy; nitro; carbamoyl; trifluoromethyl; phenoxy; benzyloxy; alkaryl; arylalkyl; carbamate; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; heteroalkyl; alkyltriphenylphosphonium; heterocyclyl; acyl halide [—COX, where X is selected from F, Cl, Br, and I]; carbonyl [—COR, where R selected from (C 1-6 )alkyl; and (C 2-6 )alkenyl]; aldehyde (—CHO); ester [—OC(═O)R, —ROC(═O)R′, RC(═O)OR′, —C(═O)OR′, where R and R′ is selected from (C 1-14 )alkyland (C 2-14 )alkenyl; carbonate ester [—OCOOR, where R is selected from (C 1-6 )alkyland (C 1-6 )alkenyl; carboxyl (—COOH); amide [—CONR′R″, where R′ and R″ is selected from hydrogen; alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; (C 2-4 )alkenyl; amines [—NR′R″, where R′ and R″ is selected from hydrogen; (C 1-6 )alkyland (C 2-6 )alkenyl; cyanate (—OCN); isocynate (—NCO); nitrate (—ONO 2 ); nitrile (—CN); isonitrile (—NC); nitroso (—NO); oxime (—CH═NOH); borono —B(OH) 2 ; borono and boronate [—B(OR′)(R″), where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; borinate [—B(R′)(OR″), where R′ and R″ is selected from H; (C 1-6 )alkyl and (C 2-6 )alkenyl; phosophino [—PR 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphate [—OP(═O)(OR) 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphono [—RP(═O)(OH), where R is selected from (C 1-6 )alkyl and (C 2-6 )alkenyl; thiol (—SH); thioalkyl; alkylthio; sulfide [—SR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; disulfide [—SSR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl, sulfonamide; sulfinyl [—S(═O)R, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; sulfino (—SO 2 H); sulfo (—SO 3 H); thiocyanate; isothiocyanate; carbonothioyl [—C(═S)R where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; 
 wherein R 2  and R 4  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; wherein R 4  and R 5  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; 
 wherein R 4  and R 6  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; and wherein R 4  and R 5  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring. 
 
     
     
         7 . The method of  claim 5 , wherein the niclosamide or niclosamide derivative has the structure of Formula 2: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 where R 7 , R 8 , R 9 , R 10 , R 11 , R 12  are independently selected from the group consisting of a H; F; Cl; Br; I; OH; ketone (═O); (C 1-6 )alkyl; (C 2-6 )alkenyl; (C 2-6 )alkynyl; ether [—OR, where R can include (C 1-6 )alkyl; aralkyl; alkaryl; halogenated alkyl; heteroalkyl; aryl; heterocyclyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxyalkyl; aminoalkyl; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; acylamino; hydroxyl; alkoxy; alkoxyalkyl; aryloxy; arylalkoxy; acyloxy; nitro; carbamoyl; trifluoromethyl; phenoxy; benzyloxy; alkaryl; arylalkyl; carbamate; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; heteroalkyl; alkyltriphenylphosphonium; heterocyclyl; acyl halide [—COX, where X is selected from F, Cl, Br, and I]; carbonyl [—COR, where R selected from (C 1-6 )alkyl; and (C 2-6 )alkenyl]; aldehyde (—CHO); ester [—OC(═O)R, —ROC(═O)R′, RC(═O)OR′, —C(═O)OR′, where R and R′ is selected from (C 1-14 )alkyland (C 2-14 )alkenyl; carbonate ester [—OCOOR, where R is selected from (C 1-6 )alkyland (C 1-6 )alkenyl; carboxyl (—COOH); amide [—CONR′R″, where R′ and R″ is selected from hydrogen; alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; (C 2-4 )alkenyl; amines [—NR′R″, where R′ and R″ is selected from hydrogen; (C 1-6 )alkyland (C 2-6 )alkenyl; cyanate (—OCN); isocynate (—NCO); nitrate (—ONO 2 ); nitrile (—CN); isonitrile (—NC); nitroso (—NO); oxime (—CH═NOH); borono —B(OH) 2 ; borono and boronate [—B(OR′)(R″), where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; borinate [—B(R′)(OR″), where R′ and R″ is selected from H; (C 1-6 )alkyl and (C 2-6 )alkenyl; phosophino [—PR 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphate [—OP(═O)(OR) 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphono [—RP(═O)(OH), where R is selected from (C 1-6 )alkyl and (C 2-6 )alkenyl; thiol (—SH); thioalkyl; alkylthio; sulfide [—SR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; disulfide [—SSR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl, sulfonamide; sulfinyl [—S(═O)R, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; sulfino (—SO 2 H); sulfo (—SO 3 H); thiocyanate; isothiocyanate; carbonothioyl [—C(═S)R where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; 
 wherein R 7  and R 10  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2 -s)alkene ring; and wherein R 4  and R 5  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; 
 wherein R 8  and R 10  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2 -s)alkene ring; wherein R 4  and R 5  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; 
 wherein R 10  and R 11  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring; and wherein R 4  and R 5  can be bonded together to form an (C 1-8 )alkane ring and/or (C 2-8 )alkene ring. 
 
     
     
         8 . The method of  claim 5 , wherein the niclosamide or niclosamide derivative has the structure of Formula 3: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 where R 13  can include (C 1-14 )alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; and (C 2-14 )alkenyl, such as ethenyl, propenyl, butenyl, where the double bond can be located at any position in the alkenyl carbon chain, including any alkenyl conformational isomers. 
 
     
     
         9 . The method of  claim 5 , wherein the niclosamide or niclosamide derivative has the structure of Formula 4: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 1 , wherein the at least one compound comprises an emricasan compound, and wherein the emricasan compound comprises:
 (a) emricasan,   (b) an emricasan derivative,   (c) a prodrug or metabolite of (a) or (b), or   (d) a pharmaceutically acceptable salt of (a), (b), or (c).   
     
     
         11 . The method of  claim 10 , wherein the emricasan or emricasan derivative has the structure of Formula 5: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 where R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , and R 34  are independently selected from the group consisting of a H; F; Cl; Br; I; OH; ketone (═O); (C 1-6 )alkyl; (C 2-6 )alkenyl; (C 2-6 )alkynyl; ether [—OR, where R can include (C 1-6 )alkyl; aralkyl; alkaryl; halogenated alkyl; heteroalkyl; aryl; heterocyclyl; cycloalkyl; cycloalkenyl; cycloalkynyl; hydroxyalkyl; aminoalkyl; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; acylamino; hydroxyl; alkoxy; alkoxyalkyl; aryloxy; arylalkoxy; acyloxy; nitro; carbamoyl; trifluoromethyl; phenoxy; benzyloxy; alkaryl; arylalkyl; carbamate; amino; alkylamino; arylamino; dialkylamino; alkylarylamino; diarylamino; heteroalkyl; alkyltriphenylphosphonium; heterocyclyl; acyl halide [—COX, where X is selected from F, Cl, Br, and I]; carbonyl [—COR, where R selected from (C 1-6 )alkyl; and (C 2-6 )alkenyl]; aldehyde (—CHO); ester [—OC(═O)R, —ROC(═O)R′, RC(═O)OR′, —C(═O)OR′, where R and R′ is selected from (C 1-14 )alkyland (C 2-14 )alkenyl; carbonate ester [—OCOOR, where R is selected from (C 1-6 )alkyland (C 1-6 )alkenyl; carboxyl (—COOH); amide [—CONR′R″, where R′ and R″ is selected from hydrogen; alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl; (C 2-4 )alkenyl; amines [—NR′R″, where R′ and R″ is selected from hydrogen; (C 1-6 )alkyland (C 2-6 )alkenyl; cyanate (—OCN); isocynate (—NCO); nitrate (—ONO 2 ); nitrile (—CN); isonitrile (—NC); nitroso (—NO); oxime (—CH═NOH); borono —B(OH) 2 ; borono and boronate [—B(OR′)(R″), where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; borinate [—B(R′)(OR″), where R′ and R″ is selected from H; (C 1-6 )alkyl and (C 2-6 )alkenyl; phosophino [—PR 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphate [—OP(═O)(OR) 2 , where R is selected from H; (C 1-6 )alkyl; and (C 2-6 )alkenyl; phosphono [—RP(═O)(OH), where R is selected from (C 1-6 )alkyl and (C 2-6 )alkenyl; thiol (—SH); thioalkyl; alkylthio; sulfide [—SR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; disulfide [—SSR, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl, sulfonamide; sulfinyl [—S(═O)R, where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; sulfino (—SO 2 H); sulfo (—SO 3 H); thiocyanate; isothiocyanate; carbonothioyl [—C(═S)R where R is selected from (C 1-6 )alkyland (C 2-6 )alkenyl; 
 wherein R 23  and R 24  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring; wherein R 23  and R 25  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring; where R 24  and R 26  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring; wherein R 27  and R 30  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene; wherein R 28  and R 29  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring; and wherein R 27  and R 30  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring, such as a five-membered ring or a six-membered ring; and wherein R 29  and R 30  can be bonded together to form an (C 2-8 )alkane ring and/or (C 2-8 )alkene ring. 
 
     
     
         12 . The method of  claim 1 , wherein the at least one compound comprises a combination of the niclosamide compound and the emricasan compound, and wherein the niclosamide compound and the emricasan compound are administered simultaneously, together within the same composition or in separate compositions. 
     
     
         13 . The method of  claim 1 , wherein the at least one compound comprises a combination of the niclosamide compound and the emricasan compound, and wherein the niclosamide compound and the emricasan compound are administered consecutively in any order. 
     
     
         14 . The method of  claim 1 , wherein the at least one compound comprises the CDK inhibitor, and the CDK inhibitor has a structure shown in  FIG. 11  (PHA-690509 or a derivative thereof),  FIG. 12  (Alvocidib or a derivative thereof),  FIG. 13  (PHA-793887 or a derivative thereof),  FIG. 14  (Dinaciclib or a derivative thereof),  FIG. 15  (Seliciclib or a derivative thereof), or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         15 . The method of  claim 1 , wherein the at least one compound comprises the CDK inhibitor, and the CDK inhibitor has a structure shown in  FIG. 16 , or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1 , wherein the at least one compound comprises a CDK inhibitor, and the CDK inhibitor is selected from among Alvocidib, Kenpaullone, Olomoucine, Purvalanol A, Purvalanol B, Seliciclib, NU-6027, Indirubin, Flavopiridol, AT7519, PD-0332991, SNS-032, PHA-793887, PHA-690509, RGB-286147, BS-194, BS-181, AZD-5438, R-547, Dinaciclib, Milciclib, BMS-265246, 7-Hydroxystaurosporine, CGP-60474, CDK9 inhibitor, NU-6102, Fascaplysin, Cdk4/6 Inhibitor IV, or a prodrug, metabolite, derivative, or pharmaceutically acceptable salt of any of the foregoing. 
     
     
         17 . The method of  claim 1 , wherein the at least one compound comprises a combination of the CDK inhibitor and the emricasan compound, and wherein the CDK inhibitor and the emricasan compound are administered simultaneously, together within the same composition or in separate compositions. 
     
     
         18 . The method of  claim 1 , wherein the at least one compound comprises a combination of the CDK inhibitor and an emricasan compound, and wherein the CDK inhibitor and the emricasan compound are administered consecutively in any order. 
     
     
         19 . The method of  claim 1 , wherein the subject has the Flavivirus infection at the time of said administering, and the at least one compound is administered as therapy. 
     
     
         20 . The method of  claim 19 , further comprising, prior to said administering, identifying the subject as having the Flavivirus infection. 
     
     
         21 . The method of  claim 20 , wherein said identifying comprises assaying a biological sample obtained from the subject for the presence of Flavivirus nucleic acids or Flavivirus proteins. 
     
     
         22 . The method of  claim 21 , wherein said assaying comprises use of reverse transcriptase-polymerase chain reaction (RT-PCR), immunological assay, or Plaque-reduction neutralization testing (PRNT). 
     
     
         23 . The method of  claim 1 , wherein the subject does not have the Flavivirus infection at the time of said administering, and the at least one compound is administered as prophylaxis. 
     
     
         24 . The method of  claim 1 , wherein the at least one compound is administered orally, nasally, rectally, parenterally, subcutaneously, intramuscularly, or intravascularly. 
     
     
         25 . The method of  claim 1 , further comprising administering an additional agent for treating or preventing Flavivirus infection, or a symptom thereof, in the same formulation as at least one compound, or in a separate formulation before, during, or after administration of the at least one compound. 
     
     
         26 . The method of  claim 1 , wherein said administering comprises administering a composition to the subject, wherein the composition comprises the at least one compound and a pharmaceutically acceptable buffer, carrier, or diluent. 
     
     
         27 . A method for inhibiting Flavivirus infection in human or non-human animal cells in vitro or in vivo, said method comprising contacting an effective amount of at least one compound to a human or non-human animal cell in vitro or in vivo before or after exposure of the cell to Flavivirus, wherein the at least one compound inhibits Flavirus infection or suppresses Flavivirus-induced caspase-3 activity, and wherein the at least one compound comprises:
 (a) a niclosamide compound, or   (b) an emricasan compound, or   (c) a cyclin-dependent kinase (CDK) inhibitor, or   (d) a proteasome inhibitor, or   (e) a compound selected from among Teriflunomide, Hydroxocobalamin, Ensulizole, Tenonitrozole, Isoliquiritigenin, Nitazoxanide, Febuxostat, Leflunomide, Vidofludimus, SB-366791, Emodin, Diphenyl isophthalate, Benzoylpas, Fenobam, Indobufen, 2-(2H-Benzotriazol-2-yl)-4-methylphenol, Tiaprofenic acid, Flufenamic acid, Vitamin B12, Cinanserin, 5-Nitro-2-(3-phenylpropylamino)benzoic acid, Veliflapon, Thiabendazole, SIB 1893, Anethole trithione, Naringenin, Phenazopyridine, Fanetizole, Terazosin, Diacerein, CAY10505, Hesperetin, Suprofen, Ketorolac tromethamine, Piperine, Pirarubicin, Piraxostat, Albendazole oxide, Tyrphostin AG 494, Genistin, Fenbufen, Apatinib, RITA, BF-170 hydrochloride, OSI-930, Tribromsalan, Pifexole, Formononetin, Ebselen, Tranilast, Benzylparaben, 2-Ethoxylethyl-p-methoxycinnamate, Baicalein, Nemorubicin, Rutaecarpine, 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 5,7-Dihydroxyflavone, Vitamin B12, Pipofezine, Flurbiprofen axetil, 2-Amino-6-nitrobenzothiazole, Malachite green oxalate, Enfenamic acid, Fenaminosulf, AS-252424, Phenserine, Epalrestat, Alizarin, Dalcetrapib, SN-38, Echinomycin, (S)-(+)-Camptothecin, BI-2536, 10-hydroxycamptothecin, Topotecan, Delanzomib, Volasertib, Ispinesib, Paclitaxel, FK-506, Emetine, AVN-944, Digoxin, Vincristine, Idarubicin, Thapsigargin, Lexibulin, Ixazomib, Cephalomannine, Mitoxantrone, MLN-2238, Demecolcine, Vinorelbine, Bardoxolone methyl, Cycloheximide, Actinomycin D, AZD-7762, PF-184, CHIR-124, Cyanein, Triptolide, KX-01, PF-477736, Epirubicin, Mycophenolate (mycophenolic acid), Daunorubicin, PIK-75, Vindesine, Torin-2, Floxuridine, Go-6976, OSU-03012, or a prodrug, metabolite, or derivative of any of the foregoing, or   
       a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         28 . The method of  claim 27 , wherein the Flavivirus is Zika virus. 
     
     
         29 . A composition comprising a combination of two or more of the following:
 (a) a niclosamide compound, or   (b) an emricasan compound, or   (c) a cyclin-dependent kinase (CDK) inhibitor, or   (d) a proteasome inhibitor, or   (e) a compound selected from among Teriflunomide, Hydroxocobalamin, Ensulizole, Tenonitrozole, Isoliquiritigenin, Nitazoxanide, Febuxostat, Leflunomide, Vidofludimus, SB-366791, Emodin, Diphenyl isophthalate, Benzoylpas, Fenobam, Indobufen, 2-(2H-Benzotriazol-2-yl)-4-methylphenol, Tiaprofenic acid, Flufenamic acid, Vitamin B12, Cinanserin, 5-Nitro-2-(3-phenylpropylamino)benzoic acid, Veliflapon, Thiabendazole, SIB 1893, Anethole trithione, Naringenin, Phenazopyridine, Fanetizole, Terazosin, Diacerein, CAY10505, Hesperetin, Suprofen, Ketorolac tromethamine, Piperine, Pirarubicin, Piraxostat, Albendazole oxide, Tyrphostin AG 494, Genistin, Fenbufen, Apatinib, RITA, BF-170 hydrochloride, OSI-930, Tribromsalan, Pifexole, Formononetin, Ebselen, Tranilast, Benzylparaben, 2-Ethoxylethyl-p-methoxycinnamate, Baicalein, Nemorubicin, Rutaecarpine, 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 5,7-Dihydroxyflavone, Vitamin B12, Pipofezine, Flurbiprofen axetil, 2-Amino-6-nitrobenzothiazole, Malachite green oxalate, Enfenamic acid, Fenaminosulf, AS-252424, Phenserine, Epalrestat, Alizarin, Dalcetrapib, SN-38, Echinomycin, (S)-(+)-Camptothecin, BI-2536, 10-hydroxycamptothecin, Topotecan, Delanzomib, Volasertib, Ispinesib, Paclitaxel, FK-506, Emetine, AVN-944, Digoxin, Vincristine, Idarubicin, Thapsigargin, Lexibulin, Ixazomib, Cephalomannine, Mitoxantrone, MLN-2238, Demecolcine, Vinorelbine, Bardoxolone methyl, Cycloheximide, Actinomycin D, AZD-7762, PF-184, CHIR-124, Cyanein, Triptolide, KX-01, PF-477736, Epirubicin, Mycophenolate (mycophenolic acid), Daunorubicin, PIK-75, Vindesine, Torin-2, Floxuridine, Go-6976, OSU-03012, or a prodrug, metabolite, or derivative of any of the foregoing, or   
       a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         30 . A composition comprising:
 (a) a niclosamide compound, or   (b) an emricasan compound, or   (c) a cyclin-dependent kinase (CDK) inhibitor, or   (d) a proteasome inhibitor, or   (e) a compound selected from among Teriflunomide, Hydroxocobalamin, Ensulizole, Tenonitrozole, Isoliquiritigenin, Nitazoxanide, Febuxostat, Leflunomide, Vidofludimus, SB-366791, Emodin, Diphenyl isophthalate, Benzoylpas, Fenobam, Indobufen, 2-(2H-Benzotriazol-2-yl)-4-methylphenol, Tiaprofenic acid, Flufenamic acid, Vitamin B12, Cinanserin, 5-Nitro-2-(3-phenylpropylamino)benzoic acid, Veliflapon, Thiabendazole, SIB 1893, Anethole trithione, Naringenin, Phenazopyridine, Fanetizole, Terazosin, Diacerein, CAY10505, Hesperetin, Suprofen, Ketorolac tromethamine, Piperine, Pirarubicin, Piraxostat, Albendazole oxide, Tyrphostin AG 494, Genistin, Fenbufen, Apatinib, RITA, BF-170 hydrochloride, OSI-930, Tribromsalan, Pifexole, Formononetin, Ebselen, Tranilast, Benzylparaben, 2-Ethoxylethyl-p-methoxycinnamate, Baicalein, Nemorubicin, Rutaecarpine, 2-Methyl-6-(phenylethynyl)pyridine (MPEP), 5,7-Dihydroxyflavone, Vitamin B12, Pipofezine, Flurbiprofen axetil, 2-Amino-6-nitrobenzothiazole, Malachite green oxalate, Enfenamic acid, Fenaminosulf, AS-252424, Phenserine, Epalrestat, Alizarin, Dalcetrapib, SN-38, Echinomycin, (S)-(+)-Camptothecin, BI-2536, 10-hydroxycamptothecin, Topotecan, Delanzomib, Volasertib, Ispinesib, Paclitaxel, FK-506, Emetine, AVN-944, Digoxin, Vincristine, Idarubicin, Thapsigargin, Lexibulin, Ixazomib, Cephalomannine, Mitoxantrone, MLN-2238, Demecolcine, Vinorelbine, Bardoxolone methyl, Cycloheximide, Actinomycin D, AZD-7762, PF-184, CHIR-124, Cyanein, Triptolide, KX-01, PF-477736, Epirubicin, Mycophenolate (mycophenolic acid), Daunorubicin, PIK-75, Vindesine, Torin-2, Floxuridine, Go-6976, OSU-03012, or a prodrug, metabolite, or derivative of any of the foregoing, or   
       a pharmaceutically acceptable salt of any of the foregoing, and
 an additional agent effective for the treatment of one or more symptoms of Flavivirus infection.