title: Pradimicin S, a highly soluble nonpeptidic small-size carbohydrate-binding antibiotic, is an anti-HIV drug lead for both microbicidal and systemic use.
abstract: Pradimicin S (PRM-S) is a highly water-soluble, negatively charged derivative of the antibiotic pradimicin A (PRM-A) in which the terminal xylose moiety has been replaced by 3-sulfated glucose. PRM-S does not prevent human immunodeficiency virus (HIV) adsorption on CD4(+) T cells, but it blocks virus entry into its target cells. It inhibits a wide variety of HIV-1 laboratory strains and clinical isolates, HIV-2, and simian immunodeficiency virus (SIV) in various cell culture systems (50% and 90% effective concentrations [EC(50)s and EC(90)s] invariably in the lower micromolar range). PRM-S inhibits syncytium formation between persistently HIV-1- and SIV-infected cells and uninfected CD4(+) T lymphocytes, and prevents dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-mediated HIV-1 and SIV capture and subsequent virus transmission to CD4(+) T cells. Surface plasmon resonance (SPR) studies revealed that PRM-S strongly binds to gp120 in a Ca(2+)-dependent manner at an affinity constant (K(D)) in the higher nanomolar range. Its anti-HIV activity and HIV-1 gp120-binding properties can be dose-dependently reversed in the presence of an (alpha-1,2)mannose trimer. Dose-escalating exposure of HIV-1-infected cells to PRM-S eventually led to the isolation of mutant virus strains that had various deleted N-glycosylation sites in the envelope gp120 with a strong preference for the deletion of the high-mannose-type glycans. Genotypic resistance development occurred slowly, and significant phenotypic resistance occurred only after the sequential appearance of up to six mutations in gp120, pointing to a high genetic barrier of PRM-S. The antibiotic is nontoxic against a variety of cell lines, is not mitogenic, and does not induce cytokines and chemokines in peripheral blood mononuclear cells as determined by the Bio-Plex human cytokine 27-plex assay. It proved stable at high temperature and low pH. Therefore, PRM-S may qualify as a potential anti-HIV drug candidate for further (pre)clinical studies, including its microbicidal use.
authors.affiliation: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.be
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Katrien O
authors.initials: KO
authors.lastname: François
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Bart
authors.initials: B
authors.lastname: Hoorelbeke
authors.forename: Marleen
authors.initials: M
authors.lastname: Renders
authors.forename: Joeri
authors.initials: J
authors.lastname: Auwerx
authors.forename: Sandra
authors.initials: S
authors.lastname: Liekens
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Oki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
mesh_terms: D018943:Anthracyclines / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D018938:Caco-2 Cells; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D024882:Drug Resistance, Viral / Q000235:genetics; D004355:Drug Stability; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015498:HIV-2 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015302:Simian Immunodeficiency Virus / Q000187:drug effects; D012995:Solubility; D053586:Virus Internalization / Q000187:drug effects; D000095643:Pradimicins and Benanomicins
chemical_list: D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D018925:Chemokines; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; C058036:pradimicin A; D000095643:Pradimicins and Benanomicins; C080896:pradimicin S