Muramyl peptide derivatives
Inventors
Ella, Krishna Murthy • Brunda, Ganneru • Kumar, Halmuthur Mahabalarao Sampath • Reddy, Paturu Rama Subba
Assignees
Council of Scientific and Industrial Research CSIR • Bharat Biotech International Ltd
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Publication Number
US-12134664-B2
Publication Date
2024-11-05
Expiration Date
Abstract
The invention is directed to Muramyl Dipeptide (MDP) derivative compounds of structural Formula-VIII, a process for synthesis, intermediates used in the synthesis and use thereof: wherein, R can be a linear or branched alkyl, an aryl, a substituted aryl, or an 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 a muramyl dipeptide (MDP) derivative compound having Formula-VIII in which substituent R is defined. The substituent R is selected from linear alkyl, branched alkyl, aryl, substituted aryl, or alkoxy alkyl, with one set of embodiments requiring 4 or more carbons and another set requiring 3 or more carbons.
The disclosed invention relates to a muramyl dipeptide derivative produced by peptide coupling and subsequent deprotection to obtain a muramyl dipeptide of Formula-VIII, specifically MDP-ET (Formula-VIII, R=ethyl). The process description specifies use of Scheme-A peptide coupling to reach intermediates (II–VIII), followed by removal of protecting groups through acid treatment and hydrogenolysis.
The disclosure directs the compound class to vaccine adjuvants and immunogenic composition contexts, linking the muramyl dipeptide derivative to immunomodulatory activity. It reports MDP-ET as an NOD2-stimulating adjuvant with NF-κB activation in HEK-Blue Human NOD2 reporter cells, and it further reports safety-related evaluations, immunogenicity, and antibody-enhancing effects in the presence of vaccine antigens.
Claims Coverage
The independent claims cover muramyl dipeptide compounds defined by structural selection and by the substituent R, with three independent claim groups across the items. The claim family also extends the compounds into immunogenic compositions and vaccines by pairing them with enumerated antigen types and, where specified, infectious pathogen categories.
Muramyl dipeptide selected from a group of chemical structures
A compound comprising a muramyl dipeptide with a formula selected from the group consisting of the following chemical structures.
Muramyl dipeptide with linear alkyl, aryl, substituted aryl, or alkoxy alkyl R
A compound comprising a muramyl dipeptide of the formula, wherein R is a linear alkyl, aryl, substituted aryl or alkoxy alkyl with 4 or more carbons.
Muramyl dipeptide with branched alkyl, aryl, substituted aryl, or alkoxy alkyl R
A compound comprising a muramyl dipeptide of the formula, wherein R is a branched alkyl, aryl, substituted aryl or alkoxy alkyl with 3 or more carbons.
Overall, the claims provide compound-level coverage for muramyl dipeptide derivatives defined either by selection from a structure group or by Formula-VIII with R constrained to linear or branched alkyl, aryl, substituted aryl, or alkoxy alkyl options with specified carbon thresholds. The dependent claim set extends this compound scope to immunogenic compositions and vaccines by incorporating live attenuated, inactivated, subunit, conjugate, recombinant, and infectious-pathogen antigens, with infectious pathogens categorized as bacterium, virus, or mammalian pathogen.
Stated Advantages
MDP-ET is reported to act as an NOD2-stimulating adjuvant with measured NF-κB activation in HEK-Blue Human NOD2 reporter cells.
Reduced pyrogenicity while retaining immunomodulatory activity as vaccine adjuvants.
The document reports safety-related measurements including cytotoxicity (MTT) and in-vitro pyrogenicity via PBMC cytokines.
The document reports immunogenicity and antibody enhancement, including increases in antibody titers and humoral/cell-mediated immune responses with vaccine antigens.
Documented Applications
Use of MDP-ET as an NOD2-stimulating adjuvant in the context of vaccine antigens, with reported antibody-enhancing immunogenicity (including humoral and cell-mediated response) in vivo.
Vaccine formulations using the disclosed MDP derivative compounds as adjuvants with vaccine antigens including live attenuated, inactivated, subunit, conjugate, recombinant, and infectious-pathogen antigens.
Use of immunogenic compositions and vaccines with infectious-pathogen antigens where infectious pathogens are categorized to include bacterium, virus, or mammalian pathogen.
Evaluation of MDP-ET in HEK-Blue Human NOD2 reporter cells for NOD2 stimulation (NF-κB activation) and reported EC50.
In-vitro safety-related evaluations including cytotoxicity (MTT) and pyrogenicity via PBMC cytokines.
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