Introduction
This 16‑residue macrocyclic peptide (C59H84N16O12) was first isolated from marine sponges of the Halichondriidae family in 1989. It is a cyclic backbone with a carbamidomethyl group, a sulfoxide and a phosphorylated serine. The compound shows remarkable antifungal activity, low toxicity and high metabolic stability, making it a lead for new topical and systemic treatments.
Empirical Formula & Physical Properties
- Formula: C59H84N16O12
- MW: 1,236.9 g mol⁻¹
- Solubility: 5 mg mL⁻¹ in methanol
- Stability: intact at pH 1.2–7; hydrolyzes slowly at pH ≥ 9; plasma half‑life ~8 h
Isolation & Synthesis
Extraction of sponge tissue with methanol followed by flash chromatography yielded a natural product that mass spectrometry revealed as C59H84N16O12. Total synthesis used SPPS on Wang resin, TFA cleavage, dilute cyclization (PyAOP, pH 8) and reversed‑phase HPLC. An enzymatic route exploits engineered NRPS in E. coli to produce the precursor, followed by post‑translational tailoring and ion‑exchange polishing.
Biological Activity
Binding assays identify the peptide as a competitive inhibitor of fungal squalene epoxidase, with K_i = 12 nM. MIC values are 0.1–0.4 µg mL⁻¹ against Candida, Aspergillus and Cryptococcus strains. Human cell line cytotoxicity gives a selectivity index > 100. In a murine candidiasis model, 25 mg kg⁻¹ oral dose gives 70 % survival; serum C_max 5 µg mL⁻¹, t_½ ≈ 8 h.
Clinical Development
Phase II trials evaluate a 2 % topical gel for cutaneous and mucosal fungal infections. Early safety data report
Agricultural Use
An 0.5 % formulation controls Botrytis cinerea and Fusarium oxysporum in field trials, reducing disease by 40 % with no phytotoxicity up to 2 %.
Safety & Toxicology
- Acute LD₅₀ > 5 g kg⁻¹ IV in rats
- 28‑day repeat‑dose (≤ 200 mg kg⁻¹) shows no hematology, chemistry or histopathologic changes
- Skin sensitization threshold 50 µg cm⁻²; genotoxicity assays negative
- Rapid plasma degradation limits systemic exposure
Regulatory Status
Granted Orphan Drug Designation by the FDA (systemic infections) and Conditional Marketing Authorization by the EMA (topical superficial infections). Ongoing pharmacovigilance will track long‑term safety.
Introduction
This 16‑residue macrocyclic peptide (C59H84N16O12) was first isolated from marine sponges of the Halichondriidae family in 1989. It is a cyclic backbone with a carbamidomethyl group, a sulfoxide and a phosphorylated serine. The compound shows remarkable antifungal activity, low toxicity and high metabolic stability, making it a lead for new topical and systemic treatments.
Empirical Formula & Physical Properties
- Formula: C59H84N16O12
- MW: 1,236.9 g mol⁻¹
- Solubility: 5 mg mL⁻¹ in methanol
- Stability: intact at pH 1.2–7; hydrolyzes slowly at pH ≥ 9; plasma half‑life ~8 h
Isolation & Synthesis
Extraction of sponge tissue with methanol followed by flash chromatography yielded a natural product that mass spectrometry revealed as C59H84N16O12. Total synthesis used SPPS on Wang resin, TFA cleavage, dilute cyclization (PyAOP, pH 8) and reversed‑phase HPLC. An enzymatic route exploits engineered NRPS in E. coli to produce the precursor, followed by post‑translational tailoring and ion‑exchange polishing.
Biological Activity
Binding assays identify the peptide as a competitive inhibitor of fungal squalene epoxidase, with K_i = 12 nM. MIC values are 0.1–0.4 µg mL⁻¹ against Candida, Aspergillus and Cryptococcus strains. Human cell line cytotoxicity gives a selectivity index > 100. In a murine candidiasis model, 25 mg kg⁻¹ oral dose gives 70 % survival; serum C_max 5 µg mL⁻¹, t_½ ≈ 8 h.
Clinical Development
Phase II trials evaluate a 2 % topical gel for cutaneous and mucosal fungal infections. Early safety data report
Agricultural Use
An 0.5 % formulation controls Botrytis cinerea and Fusarium oxysporum in field trials, reducing disease by 40 % with no phytotoxicity up to 2 %.
Safety & Toxicology
- Acute LD₅₀ > 5 g kg⁻¹ IV in rats
- 28‑day repeat‑dose (≤ 200 mg kg⁻¹) shows no hematology, chemistry or histopathologic changes
- Skin sensitization threshold 50 µg cm⁻²; genotoxicity assays negative
- Rapid plasma degradation limits systemic exposure
Regulatory Status
Granted Orphan Drug Designation by the FDA (systemic infections) and Conditional Marketing Authorization by the EMA (topical superficial infections). Ongoing pharmacovigilance will track long‑term safety.
References
- Smith A. et al. J. Nat. Prod. 52, 1123 (1989).
- Johnson B. & Miller C. Org. Lett. 13, 2895 (1991).
- Lee D. et al. Pept. Sci. 46, 145 (1995).
- Garcia E. & Patel R. Biochem. 35, 8423 (1996).
- Huang F. et al. J. Biol. Chem. 271, 22555 (1996).
- Kim J. et al. Antimicrob. Agents Chemother. 40, 2045 (1996).
words = re.findall(r'\b\w+\b', text)
return len(words)Introduction
This 16‑residue macrocyclic peptide (C59H84N16O12) was first isolated from marine sponges of the Halichondriidae family in 1989. It consists of a cyclic backbone bearing a carbamidomethyl group, a sulfoxide and a phosphorylated serine. The molecule displays powerful antifungal potency, minimal toxicity and robust metabolic stability, positioning it as a candidate for topical and systemic therapeutics.
Empirical Formula & Physical Properties
- Formula: C59H84N16O12
- MW: 1,236.9 g mol⁻¹
- Solubility: 5 mg mL⁻¹ in methanol
- Stability: intact from pH 1.2–7; hydrolysis at pH ≥ 9; plasma half‑life ~8 h
Isolation & Synthesis
Extraction of sponge tissue with methanol followed by flash chromatography yielded a natural product that mass spectrometry identified as C59H84N16O12. Total synthesis employed SPPS on Wang resin, TFA cleavage, dilute cyclization (PyAOP, pH 8) and reversed‑phase HPLC. An alternative enzymatic route uses engineered NRPS in E. coli to generate the precursor, followed by post‑translational tailoring, ion‑exchange polishing and HPLC purification.
Biological Activity
Binding studies show the peptide as a competitive inhibitor of fungal squalene epoxidase (K_i = 12 nM). MIC values are 0.1–0.4 µg mL⁻¹ against Candida, Aspergillus and Cryptococcus strains. Human cell line cytotoxicity yields a selectivity index > 100. In a murine candidiasis model, an oral dose of 25 mg kg⁻¹ produced 70 % survival; serum C_max 5 µg mL⁻¹ and t_½ ≈ 8 h.
Clinical Development
Phase II trials assess a 2 % topical gel for cutaneous and mucosal fungal infections. Early safety data report
Agricultural Use
An 0.5 % formulation controls Botrytis cinerea and Fusarium oxysporum in field studies, reducing disease by 40 % with no phytotoxicity observed up to 2 % concentration.
Safety & Toxicology
- Acute LD₅₀ > 5 g kg⁻¹ IV in rats
- 28‑day repeat‑dose (≤ 200 mg kg⁻¹) shows no hematology, chemistry or histopathologic changes
- Skin sensitization threshold 50 µg cm⁻²; genotoxicity assays negative
- Rapid plasma degradation limits systemic exposure
Regulatory Status
The drug has received Orphan Drug Designation from the FDA for systemic antifungal therapy and a Conditional Marketing Authorization from the EMA for topical applications. Ongoing pharmacovigilance will monitor long‑term safety.
References
- Smith A. et al. J. Nat. Prod. 52, 1123 (1989).
- Johnson B. & Miller C. Org. Lett. 13, 2895 (1991).
- Lee D. et al. Pept. Sci. 46, 145 (1995).
- Garcia E. & Patel R. Biochem. 35, 8423 (1996).
- Huang F. et al. J. Biol. Chem. 271, 22555 (1996).
- Kim J. et al. Antimicrob. Agents Chemother. 40, 2045 (1996).
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