Differentially protected orthogonal lanthionine technology

A technology of differential and protective groups, applied in the technical field of differentially protected orthogonal lanthionine, can solve the problem of not allowing the construction of molecules with overlapping rings and the like

Inactive Publication Date: 2008-10-15
ORAGENICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Most recent reports suggest that alkylation of an appropriately protected cysteine ​​with a protected β-bromoalanine can lead to the synthesis of lanthionine, but this method does not allow the construction of molecules with overlapping rings

Method used

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  • Differentially protected orthogonal lanthionine technology
  • Differentially protected orthogonal lanthionine technology
  • Differentially protected orthogonal lanthionine technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0160] Example 1: Synthesis of Differentially Protected Orthogonal Lanthionines

[0161] A. Synthesis of Fmoc-Cys

[0162] Fmoc-protected cysteine ​​( FIG. 3 , structure B) was synthesized from L-cystine in a two-step sequence as outlined in FIG. 4 . Sodium carbonate (4.6 g, 43.6 mmol) and L-cystine (5.0 g, 20.8 mmol) were dissolved in water (200 mL). The obtained solution was cooled to 10°C. FmocCl (11.85 g, 45.8 mmol) was dissolved in dioxane (80 mL), and the obtained solution was added dropwise to an aqueous solution of L-cystine. The solution was stirred at 10°C for 2 hours and allowed to gradually warm to room temperature. A sticky white precipitate was obtained which was filtered onto a sintered glass funnel. The product was triturated with diethyl ether (50 mL) and dried under vacuum for 2 days. N,N'-bis(Fmoc)-L-cystine (14.0 g, yield 98%) was obtained as a white powder.

[0163] N,N'-bis(Fmoc)-L-cystine (12.0 g, 17.5 mmol) was dissolved in methanol (300 mL). G...

Embodiment 2

[0177] Example 2: Synthesis of the lantibiotic nisin A using lanthionine 1 and 2 thing

[0178] A. Solid-phase peptide synthesis of nisin A analogs

[0179] The synthesis of a nisin A analog [SEQ ID NO: 2] according to the present invention is outlined below. This analog contains alanine substitutions to dehydroa-aminobutarine at position 33 and dehydroalanine at positions 30 and 2. Considerable evidence shows that this has no significant effect on the activity spectrum and potency of the product relative to native nisin A (Kuipers et al., (1996); Devos et al., (1995), Molecular Microbiology 17, 427-437; Sahl et al., (1995 ), European Journal of Biochemistry 230, 827-853; Bierbaum et al., (1996), Applied and Environmental Microbiology 62, 385-392).

[0180] Unless otherwise stated, all protocols are standard FmocSPPS methods reported in the literature. White (2003) Fmoc Solid Phase Peptide Synthesis, Apractical Approach, Oxford University Press, Oxford. Nisin A is synt...

Embodiment 3

[0208] Example 3: Structural and Biological Analysis of Purified Nisin A Analogs

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Abstract

The present invention provides a method of synthesizing an intramolecularly bridged polypeptide comprising at least one intramolecular bridge. The present invention further provides a method of synthesizing an intramolecularly bridged polypeptide comprising two intramolecular bridges, wherein the two intramolecular bridges form two overlapping ring, two rings in series, or two embedded rings. The present invention also provides methods for synthesizing lantibiotics, including Nisin A. Additionally, the invention provides intramolecularly bridged polypeptides synthesized by the methods disclosed herein and differentially protected orthogonal lanthionines.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Serial No. 60 / 708,086, filed August 12, 2005, and US Serial No. 60 / 808,907, filed May 26, 2006, both of which are hereby incorporated by reference in their entirety. Background of the invention [0003] During the second half of the twentieth century, the development of antibiotics revolutionized medical practice. Mortality due to infectious diseases decreased significantly during this period. Armstrong et al. (1999) PAMA. 281, 61-66. However, since 1982, deaths from infectious diseases have steadily increased, along with an increase in antibiotic-resistant pathogens. A wide variety of medically important bacteria are becoming increasingly resistant to antibiotics commonly used in the treatment of clinical infections. In the last 20 years, thousands of reports and books documenting this phenomenon have appeared in the literature. Armstrong et al., (1999) PAMA.281, 61-66; Dess...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/107C07K14/315
Inventor J·D·希尔曼R·S·奥鲁冈蒂J·L·史密斯
Owner ORAGENICS
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