title: 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.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Dirk
authors.initials: D
authors.lastname: Daelemans
authors.forename: Sigrid
authors.initials: S
authors.lastname: Hatse
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Oki
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002460:Cell Line; D018920:Coculture Techniques; D024882:Drug Resistance, Viral; D005838:Genotype; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019718:Receptors, CXCR4 / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000737:chemistry*; D000095643:Pradimicins and Benanomicins
chemical_list: D018943:Anthracyclines; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D014759:Viral Envelope Proteins; C058036:pradimicin A; D000095643:Pradimicins and Benanomicins