title: Novel Water-Soluble Amphotericin B-PEG Conjugates with Low Toxicity and Potent in Vivo Efficacy.
abstract: Systemic fungal infections are an increasingly prevalent health problem, especially among immunocompromised patients. Antifungal drug development lags far behind in comparison to other types of antimicrobial drugs. Current commercially available antifungals are limited by their insufficient potency, side effects, drug-drug interactions, developing drug-resistance, and narrow formulation options. Here, we report the preparation and evaluation of two novel PEG amide conjugates of amphotericin B (AMB (1)): AB1 (4) and AM2 (5). These compounds are nonlabile, they are prepared in only two and three synthetic steps, respectively, and they show antifungal activity against a wide range of clinical fungal isolates. Their toxicity is significantly lower, and their water solubility is up to 5000-fold higher than that of AMB (1). In vivo efficacy studies in a mouse model of systemic candidiasis showed that AM2 (5) successfully cured all the mice at concentrations above 3.5 mg/kg body weight. In conclusion, these properties make AB1 (4) and AM2 (5) promising candidates for clinical use.
authors.forename: Assaf
authors.initials: A
authors.lastname: Halperin
authors.forename: Yana
authors.initials: Y
authors.lastname: Shadkchan
authors.affiliation: Schulich Faculty of Chemistry, Israel Institute of Technology , 3200008 Technion-City, Haifa, Israel.
authors.forename: Evgeni
authors.initials: E
authors.lastname: Pisarevsky
authors.affiliation: Schulich Faculty of Chemistry, Israel Institute of Technology , 3200008 Technion-City, Haifa, Israel.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Szpilman
authors.forename: Hani
authors.initials: H
authors.lastname: Sandovsky
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
authors.forename: Itai
authors.initials: I
authors.lastname: Benhar
mesh_terms: D000666:Amphotericin B / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001230:Aspergillus / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy* / Q000382:microbiology*; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D012233:Rhizopus / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D000935:Antifungal Agents; D014867:Water; D011092:Polyethylene Glycols; D000666:Amphotericin B