Pradimicin A, a Carbohydrate-Binding Nonpeptidic Lead Compound for Treatment of Infections with Viruses with Highly Glycosylated Envelopes, Such as Human Immunodeficiency Virus

ABSTRACT Pradimicin A (PRM-A), an antifungal nonpeptidic benzonaphtacenequinone antibiotic, is a low-molecular-weight (molecular weight, 838) carbohydrate binding agent (CBA) endowed with a selective inhibitory activity against human immunodeficiency virus (HIV). It invariably inhibits representative virus strains of a variety of HIV-1 clades with X4 and R5 tropisms at nontoxic concentrations. Time-of-addition studies revealed that PRM-A acts as a true virus entry inhibitor. PRM-A specifically interacts with HIV-1 gp120 and efficiently prevents virus transmission in cocultures of HUT-78/HIV-1 and Sup T1 cells. Upon prolonged exposure of HIV-1-infected CEM cell cultures, PRM-A drug pressure selects for mutant HIV-1 strains containing N-glycosylation site deletions in gp120 but not gp41. A relatively long exposure time to PRM-A is required before drug-resistant virus strains emerge. PRM-A has a high genetic barrier, since more than five N-glycosylation site deletions in gp120 are required to afford moderate drug resistance. Such mutated virus strains keep full sensitivity to the other known clinically used anti-HIV drugs. PRM-A represents the first prototype compound of a nonpeptidic CBA lead and, together with peptide-based lectins, belongs to a conceptually novel type of potential therapeutics for which drug pressure results in the selection of glycan deletions in the HIV gp120 envelope.

[1]  F. Gago,et al.  Mutational Pathways, Resistance Profile, and Side Effects of Cyanovirin Relative to Human Immunodeficiency Virus Type 1 Strains with N-Glycan Deletions in Their gp120 Envelopes , 2006, Journal of Virology.

[2]  M. Haine,et al.  Van Damme A. , 1986 .

[3]  M. Boyd,et al.  Analysis of the interaction between the HIV-inactivating protein cyanovirin-N and soluble forms of the envelope glycoproteins gp120 and gp41. , 2000, Molecular pharmacology.

[4]  E. De Clercq,et al.  Profile of Resistance of Human Immunodeficiency Virus to Mannose-Specific Plant Lectins , 2004, Journal of Virology.

[5]  Y. Igarashi,et al.  Mannose-binding quinone glycoside, MBQ: potential utility and action mechanism. , 2004, Advances in applied microbiology.

[6]  S. Piscitelli,et al.  Antifungal Activity of the Pradimicin Derivative BMS 181184 in the Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits , 1998, Antimicrobial Agents and Chemotherapy.

[7]  E. Hudson,et al.  Development and applications of enhanced green fluorescent protein mutants. , 1998, BioTechniques.

[8]  Reed J. Harris,et al.  Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. , 1990, The Journal of biological chemistry.

[9]  L. Cavacini,et al.  Structure of the Fab Fragment of F105, a Broadly Reactive Anti-Human Immunodeficiency Virus (HIV) Antibody That Recognizes the CD4 Binding Site of HIV Type 1 gp120 , 2005, Journal of Virology.

[10]  E. De Clercq,et al.  A Novel and Efficient Approach to Discriminate between Pre- and Post-Transcription HIV Inhibitors , 2005, Molecular Pharmacology.

[11]  R. Means,et al.  A role for carbohydrates in immune evasion in AIDS , 1998, Nature Medicine.

[12]  S. Piscitelli,et al.  Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits , 1998, Antimicrobial Agents and Chemotherapy.

[13]  Y. Igarashi,et al.  Cloning and nucleotide sequence of the putative polyketide synthase genes for pradimicin biosynthesis from Actinomadura hibisca. , 1997, Bioscience, biotechnology, and biochemistry.

[14]  L. Stamatatos,et al.  Resistance of Human Immunodeficiency Virus Type 1 to the High-Mannose Binding Agents Cyanovirin N and Concanavalin A , 2005, Journal of Virology.

[15]  T. Hideshima,et al.  An IgG human monoclonal antibody that reacts with HIV-1/GP120, inhibits virus binding to cells, and neutralizes infection. , 1991, Journal of immunology.

[16]  T. Oki,et al.  Studies on the mode of antifungal action of pradimicin antibiotics. III. Spectrophotometric sequence analysis of the ternary complex formation of BMY-28864 with D-mannopyranoside and calcium. , 1993, The Journal of antibiotics.

[17]  R. Olsen,et al.  Anti-human immunodeficiency virus (HIV) agents are also potent and selective inhibitors of feline immunodeficiency virus (FIV)-induced cytopathic effect: development of a new method for screening of anti-FIV substances in vitro. , 1992, Antiviral research.

[18]  Ping Zhu,et al.  Antibody Domain Exchange Is an Immunological Solution to Carbohydrate Cluster Recognition , 2003, Science.

[19]  H. Katinger,et al.  The carbohydrate epitope of the neutralizing anti-HIV-1 antibody 2G12. , 2003, Advances in experimental medicine and biology.

[20]  L. Cavacini,et al.  Neutralization of HIV-1 by F105, a human monoclonal antibody to the CD4 binding site of gp120. , 1993, Journal of acquired immune deficiency syndromes.

[21]  N. Giri,et al.  Pradimicins: A novel class of broad-spectrum antifungal compounds , 2005, European Journal of Clinical Microbiology and Infectious Diseases.

[22]  J. Albert,et al.  Dual effect of interleukin 4 on HIV-1 expression: implications for viral phenotypic switch and disease progression. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  T. Oki,et al.  Anti-infectives: Overview Pradimicins: Potential antifungal and anti-HIV agents , 1994 .

[24]  J. Nielsen,et al.  Resistance to V3-directed neutralization caused by an N-linked oligosaccharide depends on the quaternary structure of the HIV-1 envelope oligomer. , 1996, Virology.

[25]  E. De Clercq,et al.  Mannose-Specific Plant Lectins from the Amaryllidaceae Family Qualify as Efficient Microbicides for Prevention of Human Immunodeficiency Virus Infection , 2004, Antimicrobial Agents and Chemotherapy.

[26]  N. Yamamoto,et al.  Inhibitory effect of new antibiotic, pradimincin A on infectivity, cytopathic effect and replication of human immunodeficiency virus in vitro. , 1988, The Journal of antibiotics.

[27]  Pradimicin Resistance of Yeast Is Caused by a Mutation of the Putative N-Glycosylation Sites of Osmosensor Protein Sln1 , 2005, Bioscience, biotechnology, and biochemistry.

[28]  J. Balzarini.  Targeting the glycans of gp120: a novel approach aimed at the Achilles heel of HIV. , 2005, The Lancet. Infectious diseases.

[29]  H. Katinger,et al.  The Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2G12 Recognizes a Cluster of α1→2 Mannose Residues on the Outer Face of gp120 , 2002, Journal of Virology.

[30]  J. Sodroski,et al.  Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody , 1998, Nature.

[31]  Jonathan M Gershoni,et al.  Computational prediction of the cross‐reactive neutralizing epitope corresponding to the monoclonal antibody b12 specific for HIV‐1 gp120 , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  A. Wlodawer,et al.  Proteins that bind high-mannose sugars of the HIV envelope. , 2005, Progress in biophysics and molecular biology.

[33]  M B Khalifa,et al.  BIACORE data processing: an evaluation of the global fitting procedure. , 2001, Analytical biochemistry.

[34]  M. Froeyen,et al.  Carbohydrate-binding Agents Cause Deletions of Highly Conserved Glycosylation Sites in HIV GP120 , 2005, Journal of Biological Chemistry.

[35]  S. Rusconi,et al.  Entry and fusion inhibitors of HIV , 2004 .

[36]  E. Clercq,et al.  Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4 , 1997, The Journal of experimental medicine.

[37]  E. Damme,et al.  Related mannose‐specific lectins from different species of the family Amaryllidaceae , 1988 .

[38]  A. Waring,et al.  Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins , 2005, Nature Immunology.

[39]  K. Gustafson,et al.  Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. , 2003, AIDS research and human retroviruses.

[40]  E. Damme.  Handbook of plant lectins : properties and biomedical applications , 1998 .

[41]  Anne-Mieke Vandamme,et al.  A genotypic resistance assay for the detection of drug resistance in the human immunodeficiency virus type 1 envelope gene. , 2005, Journal of virological methods.

[42]  J. Balzarini,et al.  Inhibition of HIV entry by carbohydrate-binding proteins. , 2006, Antiviral research.

[43]  Antu K. Dey,et al.  An Aptamer That Neutralizes R5 Strains of Human Immunodeficiency Virus Type 1 Blocks gp120-CCR5 Interaction , 2005, Journal of Virology.

[44]  N. Yamamoto,et al.  Pradimicin A inhibition of human immunodeficiency virus: attenuation by mannan. , 1990, Virology.

[45]  R. Dwek,et al.  The alpha-glucosidase inhibitor N-butyldeoxynojirimycin inhibits human immunodeficiency virus entry at the level of post-CD4 binding , 1995, Journal of virology.

[46]  R. Siliciano,et al.  Novel Single-Cell-Level Phenotypic Assay for Residual Drug Susceptibility and Reduced Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 , 2004, Journal of Virology.

[47]  H. Gendelman,et al.  Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone , 1986, Journal of virology.

[48]  H. Kawaguchi,et al.  Pradimicin, a novel class of potent antifungal antibiotics. , 1988, The Journal of antibiotics.