Methods and compositions for treating and preventing viral infections

Abstract

A method of treating or preventing a systemic viral infection in a mammal by administering a pharmaceutically acceptable composition selected from the group consisting of squalamine, an active isomer thereof, and an active analogue thereof, via a dosing regimen that delivers effective antiviral concentrations of squalamine. Also compositions for achieving the systemic antiviral effect.

1 - 23 . (canceled) 
     
     
         24 . An antiviral composition comprising:
 (a) a pharmaceutically acceptable grade of a squalamine isomer or a pharmaceutically acceptable salt thereof in an amount sufficient to produce an antiviral effect,   (b) a pharmaceutically acceptable excipient or carrier, and   (c) at least one additional active agent;   wherein the squalamine isomer has the following structure:   
       
         
           
           
               
               
           
         
         wherein:
 (i) X is 3β-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—, Z is 7β-OH, Y is 20R—CH 3 , and W is 24R-sulfate; 
 (ii) X is 3α-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—, Z is 7α-OH, Y is 20R—CH 3 , and W is 24R-sulfate; or 
 (iii) X is 3β-H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—, Z is 7α-OH, Y is 20R—CH 3 , and W is 24S-sulfate. 
 
       
     
     
         25 . The antiviral composition of  claim 24 , wherein the at least one additional active agent is selected from the group consisting of an antiviral immunological adjuvant, a viral antigen capable of eliciting an immune response, and a conventional antiviral drug 
     
     
         26 . The antiviral composition of  claim 24 , wherein the at least one additional active agent is selected from the group consisting of:
 (a) an antiretroviral agent;   (b) nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs);   (c) non-nucleoside reverse transcriptase inhibitors (NNRTIs);   (d) nucleotide or nucleoside analogues   (e) protease inhibitors (PIs);   (f) drugs based on “antisense” molecules;   (g) ribozyme antivirals;   (h) assembly inhibitors;   (i) release phase inhibitors;   (j) drugs which stimulate the immune system, which optionally are interferons or synthetic antibodies;   (k) fusion inhibitors/gp41 binders;   (l) fusion inhibitors/chemokine receptor antagonists;   (m) integrase inhibitors;   (n) hydroxyurea-like compounds;   (o) inhibitors of viral integrase;   (p) inhibitors of viral genome nuclear translocation;   (q) inhibitors of HIV entry;   (r) nucleocapsid zinc finger inhibitors;   (s) targets of HIV Tat and Rev;   (t) pharmacoenhancers;   (u) cytokines;   (v) lymphokines;   (w) an anti-inflammatory agent; and   (x) any combination thereof.   
     
     
         27 . The antiviral composition of  claim 24 , wherein the at least one additional active agent is selected from the group consisting of:
 (a) an antiviral drug selected from the group consisting of Abacavir, Aciclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Arbidol, Atazanavir, Atripla, Boceprevir, Cidofovir, Combivir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Entry inhibitors, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Fusion inhibitor, Ganciclovir, Ibacitabine, Imunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Integrase inhibitor, Interferon type III, Interferon type II, Interferon type I, Interferon, Lamivudine, Lopinavir, Loviride, Maraviroc, Molixan (NOV-205), Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nucleoside analogues, Oseltamivir Peginterferon alfa-2a, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Protease inhibitor, Raltegravir, Reverse transcriptase inhibitor, Ribavirin, Rifampicin, Rimantadine, Ritonavir, Saquinavir, Stavudine, Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, and Zidovudine;   (b) an NRTI selected from the group consisting of zidovudine/AZT, didanosinelddl, zalcitabine/ddC, stavudine/d4T, lamivudine/3TC, zidovudine/lamivudine, F-ddA, emtricitabine/FTC, dOTC (BCH-10652), Adefovir, Adefovir Dipivoxil; bis-POC PMPA, DAPD/DXG (active metabolite of DAPD); D-D4FC, GW420867, abacavir/159U89, CS-87 (3′azido-2′,3′-dideoxyuridine), and S-acyl-2-thioethyl (SATE)-bearing prodrug forms of beta-L-FD4C and P-L-FddC;   (c) an NNRTI selected from the group consisting of nevirapine, delavirdine, efavirenz, Emivirine/MKC442, AG-1549/S-1153, PNU-142721, DPC-961, DPC-963, GW420867X, CALANOLIDE A, and Propolis;   (d) a protease inhibitor selected from the group consisting of indinavir, ritonavir, saquinavir, nelfinavir, ABT378/r, BMS-232632 (an azapeptide), PNU-140690, PD-178390, BMS 232632 (an azapeptide), L-756,423 (an indinavir analog); DMP450 (a cyclic urea compound), AG-1776 (a peptidomimetic), VX-175/GW433908 (phosphate prodrug of amprenavir), CGP61755, and amprenavir;   (e) a fusion inhibitor/gp41 binder selected from the group consisting of T-20 (a peptide from residues 643-678 of the HIV gp41 transmembrane protein ectodomain) and T-1249);   (f) a fusion inhibitor/chemokine receptor antagonist selected from the group consisting of CXCR4 antagonists, AMD 3100 (a bicyclam), SDF-1, ALX404C (a cationic peptide), T22 (an 18 amino acid peptide), T134, T140, CCR5 antagonists, RANTES (9-68), AOP-RANTES, NNY-RANTES, TAK-779, CCR5/CXCR4 antagonists, NSC 651016 (a distamycin analog), CCR2B antagonists, CCR3 antagonists, CCR6 antagonists, MEP-1alpha, and MIP-1beta;   (g) an integrase inhibitor selected from the group consisting of dicaffeoylquinic (DFQA) acids; L-chicoric acid (a dicaffeoyltartaric (DCTA) acid), quinalizarin (QLC), AR 177, and naphthols;   (h) a hydroxyurea-like compound selected from the group consisting of BCX-34, ribonucleotide reductase inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitors, VX-497, mycopholic acids, CellCept (mycophenolate mofetil);   (i) arylene bis(methylketone) compounds;   (j) inhibitors of HIV entry selected from the group consisting of AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100;   (k) nucleocapsid zinc finger inhibitors;   (l) pharmacoenhancers;   (m) cytokines and lymphokines selected from the group consisting of MIP-1alpha, MIP-1beta, SDF-1alpha, IL-2, aldesleukin/L2-7001, IL4, IL-10, IL-12, IL-13, interferons, IFN-alpha2a, IFN-alpha2b, IFN-beta, antagonists of TNFs, NFkappaB, GM-CSF, M-CSF, IL-10, agents that modulate immune activation, vaccines, gene-based therapies, antibodies; aryl hydrocarbon (AH) receptor agonists and antagonists, TCDD, 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, and alpha-naphthoflavone, antioxidants, gamma-L-glutamyl-L-cysteine ethyl ester (gamma-GCE);   (n) an anti-inflammatory agent selected from the group consisting of corticosteroids, nonsteroidal anti-inflammatory drugs, antihistamines, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap; and   (o) any combination thereof.   
     
     
         28 . The antiviral composition of  claim 27 , wherein:
 (a) the nucleocapsid zinc finger inhibitors are dithiane compounds;   (b) the pharmacoenhancer is ABT-378;   (c) the agents that modulate immune activation are selected from the group consisting of cyclosporine and prednisone;   (d) the vaccines are selected from the group consisting of APL 400-003, recombinant gp120, recombinant gp120 fragments, bivalent (B/E) recombinant envelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120, gp120/soluble CD4 complex, Delta JR-FL protein, branched synthetic peptide derived from discontinuous gp120 C3/C4 domain, fusion-competent immunogens, Gag vaccines, Pol vaccines, Nef vaccines, and Tat vaccines;   (e) the gene-based therapies are selected from the group consisting of genetic suppressor elements (GSEs) and intrakines; and/or   (f) the antibodies are selected from the group consisting of anti-CXCR4 antibody 12G5, anti-CCR5 antibody 2D7, anti-CCR5 antibody 5C7, anti-CCR5 antibody PA8, anti-CCR5 antibody PA9, anti-CCR5 antibody PA10, anti-CCR5 antibody PA11, anti-CCR5 antibody PA12, anti-CCR5 antibody PA14, anti-CD4 antibody Q4120, anti-CD4 antibody RPA-T4, anti-CCR3 antibody 7B11, anti-gp120 antibody 17b, anti-gp120 antibody 48d, anti-gp120 antibody 447-52D, anti-gp120 antibody 257-D, anti-gp120 antibody 268-D, anti-gp120 antibody 50.1, anti-Tat antibodies, anti-TNF-alpha antibodies, and monoclonal antibody 33A.   
     
     
         29 . The antiviral composition of  claim 24 , wherein the at least one additional active agent is an adjuvant. 
     
     
         30 . The antiviral composition of  claim 29 , wherein the adjuvant is selected from the group consisting of cytokines and/or interleukins, alum, Lipid A, including monophosphoryl lipid A, bacterial products, endotoxins, cholesterol, fatty acids, aliphatic amines, paraffinic and vegetable oils, threonyl derivative, and muramyl dipeptide, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG, MPL, nonviable preparations of  Corynebacterium, parvum , Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and a Virosomal adjuvant. 
     
     
         31 . The antiviral composition of  claim 30 , wherein the cytokine and/or interleukin is selected from the group consisting of: IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL-9, IL10, IL-11, IL12, IL13, IL-14, IL15, IIL16, IL-17, IL-18, IL-19, IL-20, IL-21, anti-CD40, CD40L, IFN-gamma, TNF-alpha, IL-1alpha, and IL-1beta. 
     
     
         32 . An antiviral composition comprising:
 (a) a pharmaceutically acceptable grade of squalamine or a pharmaceutically acceptable salt thereof in an amount sufficient to produce an antiviral effect,   (b) a pharmaceutically acceptable excipient or carrier, and   (c) at least one additional active agent.   
     
     
         33 . The antiviral composition of  claim 32 , wherein the at least one additional active agent is selected from the group consisting of an antiviral immunological adjuvant, a viral antigen capable of eliciting an immune response, and a conventional antiviral drug. 
     
     
         34 . The antiviral composition of  claim 32 , wherein the at least one additional active agent is selected from the group consisting of:
 (a) an antiretroviral agent;   (b) nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs);   (c) non-nucleoside reverse transcriptase inhibitors (NNRTIs);   (d) nucleotide or nucleoside analogues,   (e) protease inhibitors (PIs);   (f) drugs based on “antisense” molecules;   (g) ribozyme antivirals;   (h) assembly inhibitors;   (i) release phase inhibitors;   (j) drugs which stimulate the immune system, which optionally are interferons and synthetic antibodies;   (k) fusion inhibitors/gp41 binders;   (l) fusion inhibitors/chemokine receptor antagonists;   (m) integrase inhibitors;   (n) hydroxyurea-like compounds;   (o) inhibitors of viral integrase;   (p) inhibitors of viral genome nuclear translocation;   (q) inhibitors of HIV entry;   (r) nucleocapsid zinc finger inhibitors;   (s) targets of HIV Tat and Rev;   (t) pharmacoenhancers;   (u) cytokines;   (v) lymphokines;   (w) an anti-inflammatory agent; and   (x) any combination thereof.   
     
     
         35 . The antiviral composition of  claim 32 , wherein the at least one additional active agent is selected from the group consisting of:
 (a) an antiviral drug selected from the group consisting of Abacavir, Aciclovir, Acyclovir, Adefovir, Amantadine, Amprenavir, Arbidol, Atazanavir, Atripla, Boceprevir, Cidofovir, Combivir, Darunavir, Delavirdine, Didanosine, Docosanol, Edoxudine, Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Entry inhibitors, Famciclovir, Fomivirsen, Fosamprenavir, Foscarnet, Fosfonet, Fusion inhibitor, Ganciclovir, Ibacitabine, Imunovir, Idoxuridine, Imiquimod, Indinavir, Inosine, Integrase inhibitor, Interferon type III, Interferon type II, Interferon type I, Interferon, Lamivudine, Lopinavir, Loviride, Maraviroc, Molixan (NOV-205), Moroxydine, Nelfinavir, Nevirapine, Nexavir, Nucleoside analogues, Oseltamivir Peginterferon alfa-2a, Penciclovir, Peramivir, Pleconaril, Podophyllotoxin, Protease inhibitor, Raltegravir, Reverse transcriptase inhibitor, Ribavirin, Rifampicin, Rimantadine, Ritonavir, Saquinavir, Stavudine, Tenofovir, Tenofovir disoproxil, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir, Valganciclovir, Vicriviroc, Vidarabine, Viramidine, Zalcitabine, Zanamivir, and Zidovudine;   (b) an NRTI selected from the group consisting of zidovudine/AZT, didanosinelddl, zalcitabine/ddC, stavudine/d4T, lamivudine/3TC, zidovudine/lamivudine, F-ddA, emtricitabine/FTC, dOTC (BCH-10652), Adefovir, Adefovir Dipivoxil; bis-POC PMPA, DAPD/DXG (active metabolite of DAPD); D-D4FC, GW420867, abacavir/159U89, CS-87 (3′azido-2′,3′-dideoxyuridine), and S-acyl-2-thioethyl (SATE)-bearing prodrug forms of beta-L-FD4C and P-L-FddC;   (c) an NNRTI selected from the group consisting of nevirapine, delavirdine, efavirenz, Emivirine/MKC442, AG-1549/S-1153, PNU-142721, DPC-961, DPC-963, GW420867X, CALANOLIDE A, and Propolis;   (d) a protease inhibitor selected from the group consisting of indinavir, ritonavir, saquinavir, nelfinavir, ABT378/r, BMS-232632 (an azapeptide), PNU-140690, PD-178390, BMS 232632 (an azapeptide), L-756,423 (an indinavir analog); DMP450 (a cyclic urea compound), AG-1776 (a peptidomimetic), VX-175/GW433908 (phosphate prodrug of amprenavir), CGP61755, and amprenavir;   (e) a fusion inhibitor/gp41 binder selected from the group consisting of T-20 (a peptide from residues 643-678 of the HIV gp41 transmembrane protein ectodomain) and T-1249);   (f) a fusion inhibitor/chemokine receptor antagonist selected from the group consisting of CXCR4 antagonists, AMD 3100 (a bicyclam), SDF-1, ALX404C (a cationic peptide), T22 (an 18 amino acid peptide), T134, T140, CCR5 antagonists, RANTES (9-68), AOP-RANTES, NNY-RANTES, TAK-779, CCR5/CXCR4 antagonists, NSC 651016 (a distamycin analog), CCR2B antagonists, CCR3 antagonists, CCR6 antagonists, MEP-1alpha, and MIP-1beta;   (g) an integrase inhibitor selected from the group consisting of dicaffeoylquinic (DFQA) acids; L-chicoric acid (a dicaffeoyltartaric (DCTA) acid), quinalizarin (QLC), AR 177, and naphthols;   (h) a hydroxyurea-like compound selected from the group consisting of BCX-34, ribonucleotide reductase inhibitors, inosine monophosphate dehydrogenase (IMPDH) inhibitors, VX-497, mycopholic acids, CellCept (mycophenolate mofetil);   (i) arylene bis(methylketone) compounds;   (j) inhibitors of HIV entry selected from the group consisting of AOP-RANTES, NNY-RANTES, RANTES-IgG fusion protein, soluble complexes of RANTES and glycosaminoglycans (GAG), and AMD-3100;   (k) nucleocapsid zinc finger inhibitors;   (l) pharmacoenhancers;   (m) cytokines and lymphokines selected from the group consisting of MIP-1alpha, MIP-1beta, SDF-1alpha, IL-2, aldesleukin/L2-7001, IL4, IL-10, IL-12, IL-13, interferons, IFN-alpha2a, IFN-alpha2b, IFN-beta, antagonists of TNFs, NFkappaB, GM-CSF, M-CSF, IL-10, agents that modulate immune activation, vaccines, gene-based therapies, antibodies; aryl hydrocarbon (AH) receptor agonists and antagonists, TCDD, 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′-tetrachlorobiphenyl, and alpha-naphthoflavone, antioxidants, gamma-L-glutamyl-L-cysteine ethyl ester (gamma-GCE);   (n) an anti-inflammatory agent selected from the group consisting of corticosteroids, nonsteroidal anti-inflammatory drugs, antihistamines, aminoarylcarboxylic acid derivatives, arylacetic acid derivatives, arylbutyric acid derivatives, arylcarboxylic acids, arylpropionic acid derivatives, pyrazoles, pyrazolones, salicylic acid derivatives, thiazinecarboxamides, e-acetamidocaproic acid, S-adenosylmethionine, 3-amino4-hydroxybutyric acid, amixetrine, bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone, guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline, perisoxal, pifoxime, proquazone, proxazole, and tenidap; and   (o) any combination thereof.   
     
     
         36 . The antiviral composition of  claim 35 , wherein:
 (a) the nucleocapsid zinc finger inhibitors are dithiane compounds;   (b) the pharmacoenhancer is ABT-378;   (c) the agents that modulate immune activation are selected from the group consisting of cyclosporine and prednisone;   (d) the vaccines are selected from the group consisting of APL 400-003, recombinant gp120, recombinant gp120 fragments, bivalent (B/E) recombinant envelope glycoprotein, rgp120CM235, MN rgp120, SF-2 rgp120, gp120/soluble CD4 complex, Delta JR-FL protein, branched synthetic peptide derived from discontinuous gp120 C3/C4 domain, fusion-competent immunogens, Gag vaccines, Pol vaccines, Nef vaccines, and Tat vaccines;   (e) the gene-based therapies are selected from the group consisting of: genetic suppressor elements (GSEs) and intrakines;   (f) the antibodies are selected from the group consisting of anti-CXCR4 antibody 12G5, anti-CCR5 antibody 2D7, anti-CCR5 antibody 5C7, anti-CCR5 antibody PA8, anti-CCR5 antibody PA9, anti-CCR5 antibody PA10, anti-CCR5 antibody PA11, anti-CCR5 antibody PA12, anti-CCR5 antibody PA14, anti-CD4 antibody Q4120, anti-CD4 antibody RPA-T4, anti-CCR3 antibody 7B11, anti-gp120 antibody 17b, anti-gp120 antibody 48d, anti-gp120 antibody 447-52D, anti-gp120 antibody 257-D, anti-gp120 antibody 268-D, anti-gp120 antibody 50.1, anti-Tat antibodies, anti-TNF-alpha antibodies, and the monoclonal antibody 33A.   
     
     
         37 . The antiviral composition of  claim 32 , wherein the at least one additional active agent is an adjuvant. 
     
     
         38 . The antiviral composition of  claim 37 , wherein the adjuvant is selected from the group consisting of: cytokines and/or interleukins, alum, Lipid A, including monophosphoryl lipid A, bacterial products, endotoxins, cholesterol, fatty acids, aliphatic amines, paraffinic and vegetable oils, threonyl derivative, and muramyl dipeptide, alum, alum plus deoxycholate (ImmunoAg), MTP-PE (Biocine Corp.), QS21 (Genentech, Inc.), BCG, MPL, nonviable preparations of  Corynebacterium, parvum , Monophosphoryl lipid immunomodulator, AdjuVax 100a, QS-21, QS-18, CRL1005, Aluminum salts, MF-59, and a Virosomal adjuvant. 
     
     
         39 . The antiviral composition of  claim 38 , wherein the cytokine and/or interleukin is selected from the group consisting of: IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL-9, IL10, IL-11, IL12, IL13, IL-14, IL15, IIL16, IL-17, IL-18, IL-19, IL-20, IL-21, anti-CD40, CD40L, IFN-gamma, TNF-alpha, IL-1alpha, and IL-1beta.