Pradimicin A, a carbohydrate-binding nonpeptidic lead compound for treatment of infections with viruses with highly glycosylated envelopes, such as human immunodeficiency virus

Balzarini, Jan; Van Laethem, Kristel; Daelemans, Dirk; Hatse, Sigrid; Bugatti, Antonella; Rusnati, Marco; Igarashi, Yasuhiro; Oki, Toshikazu; Schols, Dominique

doi:10.1128/JVI.01404-06

Pradimicin A, a carbohydrate-binding nonpeptidic lead compound for treatment of infections with viruses with highly glycosylated envelopes, such as human immunodeficiency virus

Author:

Balzarini, Jan

Van Laethem, Kristel ; Daelemans, Dirk ; Hatse, Sigrid ; Bugatti, Antonella ; Rusnati, Marco ; Igarashi, Yasuhiro ; Oki, Toshikazu ; Schols, Dominique

Keywords:

Anthracyclines, Anti-HIV Agents, Antigens, CD4, Carbohydrate Metabolism, Cell Line, Coculture Techniques, Drug Resistance, Viral, Genotype, Glycosylation, HIV Envelope Protein gp120, HIV-1, Humans, Models, Molecular, Mutation, Receptors, CXCR4, Viral Envelope Proteins, Science & Technology, Life Sciences & Biomedicine, Virology, HUMAN MONOCLONAL-ANTIBODY, DERIVATIVE BMS 181184, CYANOVIRIN-N, ACHILLES-HEEL, PLANT-LECTINS, HIV, GP120, TYPE-1, RESISTANCE, ENTRY, CD4 Antigens, 06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences, 30 Agricultural, veterinary and food sciences, 31 Biological sciences, 32 Biomedical and clinical sciences

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.