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(12) United States Patent (10) Patent No.: US 8,193,157 B2 Balzarini Et Al

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(12) United States Patent (10) Patent No.: US 8,193,157 B2 Balzarini Et Al US0081931.57B2 (12) United States Patent (10) Patent No.: US 8,193,157 B2 Balzarini et al. (45) Date of Patent: Jun. 5, 2012 (54) ANTIVIRAL THERAPIES WO WO 97.33622 9, 1997 WO WOO3,0571.76 T 2003 (75) Inventors: Jan Balzarini, Heverlee (BE); Monika WO WOO3,061579 T 2003 Mazik, Braunschweig (DE) WO WO 2005/0244 16 * 3/2005 OTHER PUBLICATIONS (73) Assignees: K.U.Leuven Research & Development, Leuven (BE); Technische Universität Goff, PubMed Abstract (JGene Med3(6):517-28), Nov.-Dec. 2001.* Carolo Wilhelmina Zu Braunschweig, Bosseray et al., PubMed Abstract (Pathol Biol (Paris) 50(8):483-92), Braunschweig (DE) Oct. 2002. Razonable et al., PubMed Abstract (Herpes 10(3):60-5), Dec. 2003.* (*) Notice: Subject to any disclaimer, the term of this Douglas, Jr. Introduction to Viral Diseases, Cecil Textbook of Medi cine, 20th Edition, vol. 2, pp. 1739-1747, 1996.* patent is extended or adjusted under 35 Mizuochi et al., “HIV Infection and Oligosaccharides: A Novel U.S.C. 154(b) by 924 days. Approach to Preventing HIV Infection and the Onset of AIDS.” The Journal of Infection and Chemotherapy, vol. 5, No. 4, pp. 190-195, (21) Appl. No.: 12/067,681 1999. Mizutani et al., “Molecular Recognition of Carbohydrates by Zinc (22) PCT Filed: Sep. 21, 2006 Porphyrins: Lewis Acid Lewis Base Combinations as a Dominant Factor for Their Selectivity.” Journal of the American Chemical (86). PCT No.: PCT/BE2OO6/OOO104 Society, vol. 119, No. 38, pp. 8991-9001, 1997. S371 (c)(1), International Search Report and Written Opinion (PCT/BE2006/ (2), (4) Date: Mar. 21, 2008 000 104) mailed Oct. 29, 2007. International Preliminary Report on Patentability (PCT/BE2006/ (87) PCT Pub. No.: WO2007/033444 000 104) mailed Apr. 3, 2008. Office Action for Australian Patent Application No. 2006294358, PCT Pub. Date: Mar. 29, 2007 dated May 19, 2011. Uchimura et al., “Totally Synthetic Polymer with Lectin-Like Func (65) Prior Publication Data tion: Induction of Killer Cells by the Copolymer of US 2009/OO42793 A1 Feb. 12, 2009 3-Acrylamidophenylboronic Acid with N,N-Dimethylacrylamide.” Biotechnol. Bioeng. 72(3): 307-314 (2001). (30) Foreign Application Priority Data Communication for European Patent Application No. 06790 462.3, dated Jun. 9, 2011. Sep. 21, 2005 (GB) ................................... 05191 69.7 * cited by examiner (51) Int. Cl. A6 IK3I/69 (2006.01) Primary Examiner — Deepak Rao (52) U.S. Cl. ............................................ 514/23: 514/64 (74) Attorney, Agent, or Firm — Clark & Elbing LLP (58) Field of Classification Search .................... 514/23, (57) ABSTRACT 514764 See application file for complete search history. The field of the invention relates to the use of carbohydrate binding compounds as a medicine, their use to treat or prevent (56) References Cited viral infections, their use to manufacture a medicine to treator prevent viral infections and their use in a vaccination strategy. U.S. PATENT DOCUMENTS The present invention relates to the use of said compounds to 5, 192,788 A 3, 1993 Dixon et al. manufacture a medicine to treat or prevent viral infections of 6,620,805 B1 9, 2003 Takleet al. Subjects, more in particular infections with viruses having 6,960,654 B2 * 1 1/2005 Crich et al. .................. 536, 18.5 glycosilated envelop proteins such as Retroviridae (i.e. Len FOREIGN PATENT DOCUMENTS tivirinae), like HIV (human immunodeficiency virus), Fla EP O173092 3, 1986 viviridae, like HCV (hepatitis C virus), Hepadnaviridae, like JP O3/264530 11, 1991 HBV (hepatitis B virus), Coronaviridae, like SARS corona WO WO 89/11277 11, 1989 virus, and Orthomyxoviridae, like influenza A, B or C. WO WO92fO2242 2, 1992 WO WO92, 17182 10, 1992 6 Claims, 6 Drawing Sheets U.S. Patent Jun. 5, 2012 Sheet 1 of 6 US 8,193,157 B2 GC Man Ma Man Mar Man Man Man Man Ma Man Ma Man Man N / N / N / t is...ir Till Filar ff, J. faii, N ? Trimming & Processing Y^ Trimming N u? w N s 3 R cy 3 Mar city Gly ors city. 1--- Asn-1-1- -N1--- Asn--- ar/Nara ASh-ra-ra-ra GlcNAc s: A sh Gal Gal Gal GlcNAc GlcNAc GlcNAc GicNAc GlcNAc Man Man N / N / . w fit ar far N / Terminal glycosylation N / Trimming N / fif --- Earl a-r - lvia * if: 2i. GlcNA C Giri, 2 Man Gli Air. Fuc 3 Gal FuG fi”. 3 SA co Giles ^^^ Asn-1- ------ AS ---n- As N-1- Fig. 1 U.S. Patent Jun. 5, 2012 Sheet 2 of 6 US 8,193,157 B2 Figure 2 U.S. Patent Jun. 5, 2012 Sheet 3 of 6 US 8,193,157 B2 Initiation of CBA Extensive pool of -- High amount of -- Virtually no treatment free WTHIV particles WT HIV-infected efficient Natas cells Weeks rProgressive depletion Progressive depletion => t creasing amounts of of WT HIV particles of WTHIV-infected Idals against previously •Progressive appearance cells hioider immunogenic of gp120-mutated HIV •Progressive appearance gp120 epitopes particles of gp120-mutated HIV. infected cets Months Low pools of -- Severely decreased == High argurt of predominant gp120. number of predominant Palas against different Mutated HIV particles mutant HIV-infected g) 2.0 site pes cells Continuous CBA pressure Figure 3 U.S. Patent Jun. 5, 2012 Sheet 5 of 6 US 8,193,157 B2 1000 100 -A-GNA (M) -o-HHA (uM) -0-CA (M) 10 - --UDA (M) k-PRM-A (M) 0.1 !-- " - " - " - " -m-m-m- O,OOOO1 0.0001 0.001 0.01 0.1 10 100 Log compound concentration Figure 5 U.S. Patent Jun. 5, 2012 Sheet 6 of 6 US 8,193,157 B2 5 1 0.2 0.04 10 2 0.4 0.08 uol?q??u?joqueoued)silaoNØIS-OGIJ??ex.AqaunqdeoL-AIH Compound concentration Figure 6 US 8, 193,157 B2 1. 2 ANTIVIRAL THERAPES pounds are mostly used in combination therapies (HAART) wherein different classes of anti-HIV compounds are com CROSS-REFERENCE TO RELATED bined. APPLICATIONS Entry inhibitors are a relatively new class of anti-HIV compounds and the process of HIV entry into host cells This application is the U.S. National Stage of International provides different targets for the development of antiretrovi Application No. PCT/BE2006/000104, filed Sep. 21, 2006, ral drugs. Every step of HIV entry can theoretically be inhib which claims the benefit of British Patent Application No. ited, namely 1. binding of HIV to the CD4 receptor, 2. binding 0519169.7, filed Sep. 21, 2005. to coreceptors and 3. fusion of virus and cell. 10 The envelope protein of HIV is a trimer, with each of the FIELD OF THE INVENTION components consisting of 2 subunits, gp41 and gp120. The gp120 subunit of the viral envelope binds to the cellular CD4 The field of the invention relates to the use of carbohydrate molecule; this receptor binding induces conformational binding compounds as a medicine, their use to treat or prevent changes in the viral envelope protein that include exposure of viral infections, their use to manufacture a medicament to 15 a previously hidden, highly conserved domain that binds to a treat or prevent viral infections and their use in a vaccination second receptor (coreceptor). The viral coreceptors, CCR5 strategy. The present invention relates to the use of said com and CXCR4, are members of the chemokine subfamily of pounds to manufacture a medicine to treat or prevent viral 7-transmembrane domain receptors. Coreceptor binding infections of Subjects, more in particular infections with induces conformational changes in the gp41 subunit that viruses having glycosilated envelop proteins such as Retro result in the insertion of a fusion peptide into the cell mem viridae (i.e. Lentivirinae), like HIV (human immunodefi brane and the binding of gp41 helical region 1 and helical ciency virus), Flaviviridae like, HCV (hepatitis C virus), Hep region 2, which mechanically draws the viral and cell mem adnaviridae, like HBV (hepatitis B virus), Coronaviridae, like branes together and permits membrane fusion. SARS-CoV, and Orthomyxoviridae, like influenza virus A, B Enfluvirtide, a fusion inhibitor, is the only entry inhibitor and C. 25 currently approved by the US Food and Drug Administration for use as an antiretroviral agent. Basically, enfuvirtide mim BACKGROUND OF THE INVENTION ics the structure of helical region 2 of gp41, which binds with helical region 1. By binding with helical region 1, the drug Viral infections remain a major medical problem world molecule prevents binding to helical region 2 and thus pre wide because of a lack of efficient therapy, prevention or 30 vents fusion of the viral and cellular membranes. Other not vaccination strategy and because of the rapid development of yet marketed HIV-inhibiting entry inhibitors are known in the resistance. Many virusses and virus families causing prob art and they interact on different levels of the entry process. lematic disorders can be identified. The family of the Fla These include neutralizing monoclonal antibodies directed viviridae (i.e. Dengue virus, HCV. Yellow Fever virus, West against the native trimeric structure of the viral envelope; Nile virus) can cause major health problems worldwide for 35 CD4 binding inhibitors, including BMS-806 (which binds in mammals including humans. The family of the Herpesviridae a cleft of gp120 and thus prevents CD4 binding); CCR5 includes important human pathogens like Herpes simplex binding inhibitors and CXCR4 binding inhibitors (e.g., virus (HSV) type 1 and 2 and cause disorders like Herpes AMD3100); and fusion inhibitors (e.g., the enfuvirtide Labialis and Herpes Genitalis and so on. Coronaviridae now derivative, T1249). approximately comprises 15 species, causing in humans res 40 There exists a variety of carbohydrate-recognizing plant piratory infections (including Severe Acute Respiratory Syn proteins (agglutinins-lectins) that are endowed with anti-HIV drome (SARS), enteric infections and rarely neurological activity.
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