Muramyl peptide derivative compound, synthesis and uses thereof
Inventors
Ella, Krishna Murthy • Brunda, Ganneru • Kumar, Halmathur Mahabalarao Sampath • Sreekanth, Miryala
Assignees
Council of Scientific and Industrial Research CSIR • Bharat Biotech International Ltd
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Publication Number
US-10927147-B2
Publication Date
2021-02-23
Expiration Date
Abstract
The invention relates to novel Muramyl Dipeptide (MDP) derivative compound of structural Formula-VIII, a process for synthesis, intermediates used in the synthesis and use thereof.Wherein, R can be both linear and branched alkyl, aryl, substituted aryl and alkoxy alkyl. These compounds possess excellent pharmacological properties, in particular immunomodulating properties for use as adjuvant in vaccine formulations. These compounds are, particularly useful as adjuvants in vaccines.
Core Innovation
The invention relates to novel muramyl dipeptide (MDP) derivative compounds of a structural Formula-VIII, including an ethyl muramyl dipeptide derivative (MDP-ET). The compounds include an alkoxycarbonyl substituent parameter R, where R is selected from alkyl, aryl, substituted aryl, and alkoxyalkyl, and the disclosed compound is characterized by defined molecular structure.
The disclosed MDP-ET compound is characterized by infrared (IR) and 1H-NMR profiles, including specified peak positions, measurement conditions, chemical shifts, and signal multiplicities. The document also describes synthetic coupling and deprotection to obtain a muramyl dipeptide derivative of the claimed formula, including an ethyl muramyl dipeptide derivative.
The document states that the MDP derivatives show immunomodulatory properties and reduced pyrogenicity when used as vaccine adjuvants. It further reports in vitro NOD2 reporter activation, in vitro cytotoxicity and pyrogenicity evaluations, and in vivo immunogenicity and adjuvant effects including increased antigen-specific antibody titers with vaccine antigens such as HBsAg and PvRII.
Claims Coverage
The claim set includes one independent claim directed to a muramyl dipeptide of a formula, with dependent claims adding IR and 1H-NMR characterization constraints and further claims shifting to vaccine formulation use. Across the claim family, the coverage emphasizes compound identity by structural formula, compound-specific spectral profiles, and vaccine formulation elements including antigen type and an infectious-pathogen-containing component.
Muramyl dipeptide of formula
A compound comprising a muramyl dipeptide of the formula as specified.
Infrared spectral peak profile
A compound of the formula further including an IR spectral profile with specified IR peak positions.
Proton NMR profile at stated conditions
A compound defined by a specified 1H-NMR profile obtained at 300 MHz in DMSO-d6, with the given chemical shifts and multiplicities for the specified signals.
Vaccine formulation containing the compound
A vaccine formulation that includes the compound of the formula.
Vaccine antigen selection
The vaccine formulation including an antigen selected from live attenuated, inactivated, subunit, conjugate, recombinant antigens, or combinations thereof.
Infectious pathogen component for vaccine
The vaccine formulation including an infectious pathogen comprising bacteria, a virus, or a mammalian pathogen.
Overall, the claims coverage spans compound-level protection for muramyl dipeptide derivatives defined by formula and, in dependents, by explicit IR and 1H-NMR characterization profiles, and extends to vaccine formulations containing the compounds with specified antigen-type options and an infectious-pathogen class limited to bacteria, a virus, or a mammalian pathogen.
Stated Advantages
Reduced pyrogenicity
Immunomodulatory activity as vaccine adjuvants
Increased antibody titers, including an about 4-fold increase
Supports humoral and cell-mediated immune responses
In vitro NOD2 reporter activation
In vitro cytotoxicity and pyrogenicity evaluations
Reported safety and tolerability in Wistar rats, including maximum tolerated dose and lack of major lesions
Documented Applications
Use of the disclosed MDP derivative compounds as vaccine adjuvants in vaccine formulations containing vaccine antigens.
Vaccine antigen compositions including live attenuated, inactivated, subunit, conjugate, and recombinant vaccine antigens.
Vaccine formulations including an infectious pathogen component comprising bacteria, a virus, or a mammalian pathogen.
Immunogenicity and adjuvant evaluation with vaccine antigens HBsAg and Plasmodium vivax PvRII.
In vitro immunomodulation assessment via NOD2 reporter activation and cytotoxicity and pyrogenicity assessments.
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