Bioconjugates as therapeutic agent and synthesis thereof
Inventors
ROY, RAJENDRA PRASAD • SAMANTARAY, SHARMISHTHA
Assignees
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Publication Number
US-8148321-B2
Publication Date
2012-04-03
Expiration Date
Abstract
The present disclosure relates to a novel enzymatic approach according to the invention using an unprecedented sortase-catalyzed transpeptidation reaction between a substrate comprising LPXTG (SEQ ID NO: 11) peptide motif and biomolecules such as aminosugars, hydroxyamino acids, hydroxyamino acid esters, aminolipids, polyamines; nucleic acids or derivatives thereof; or any molecule having such moieties; or any compound having such moieties to obtain a bioconjugates useful for target delivery of a compound. The present disclosure provides bioconjugates obtained by the novel sortase catalysed transpeptidedation reaction.
Core Innovation
The disclosed invention provides a therapeutic and diagnostic bioconjugate useful for target delivery of a compound. The bioconjugate comprises a substrate that includes an LPXTG (SEQ ID NO: 11) peptide motif capable of recognizing sortase, together with a biomolecule that is an aminoglycoside having a 6-Deoxy-6-amino-hexose moiety.
The biomolecule is coupled to the substrate after cleavage of the glycine moiety of the LPXTG motif, so that the substrate is attached to the biomolecule via an amide bond between a resulting terminal threonyl carboxylate and the biomolecule to form the bioconjugate. Sortase-catalyzed transpeptidation/transamidation is described using the LPXTG (SEQ ID NO: 11) motif substrate, enabling covalent linking of diverse nucleophiles to form bioconjugates for therapeutic/diagnostic target delivery.
Documented examples include ligation to 6-amino-6-deoxyglucose and multiple aminoglycoside antibiotics, including kanamycin, tobramycin, ribostamycin, paromomycin, and neomycin, with reported site-of-ligation differences. The disclosure also identifies a failure with glucosamine (2-amino-2-deoxyglucose) in the described context and further encompasses therapeutic/diagnostic compositions and kits.
Claims Coverage
The independent claim covers a therapeutic and diagnostic bioconjugate useful for target delivery with a defined sortase-recognized LPXTG substrate and an aminoglycoside linked via an amide bond through a terminal threonyl carboxylate. Two inventive features are identified, with dependent-claim limitations narrowing the substrate and biomolecule selections.
LPXTG motif substrate for sortase recognition
A substrate comprising LPXTG (SEQ ID NO: 11) peptide motif capable of recognizing sortase, wherein the substrate is selected from peptides, polypeptides, proteins, glycoprotein, lipoprotein, antibodies, radionucleotides, fluorophores, ligand chromophore, and any compound comprising the LPXTG (SEQ ID NO: 11) peptide motif.
Aminoglycoside with 6-Deoxy-6-amino-hexose moiety linked via amide bond through threonyl carboxylate
A biomolecule that is an aminoglycoside having a 6-Deoxy-6-amino-hexose moiety, wherein the glycine moiety of the LPXTG (SEQ ID NO: 11) motif is cleaved and the substrate is attached to the biomolecule via an amide bond between the resulting terminal threonyl carboxylate and the biomolecule to form the bioconjugate.
Overall, the claim coverage focuses on a sortase-recognized LPXTG (SEQ ID NO: 11) substrate, cleavage of the glycine moiety within that motif, and formation of an amide bond between the resulting terminal threonyl carboxylate and an aminoglycoside biomolecule bearing a 6-Deoxy-6-amino-hexose moiety. Dependent claims further narrow the substrate by specifying particular peptide sequences and narrow the aminoglycoside/aminosugar components to named members with 6-amino-6-deoxy variants.
Stated Advantages
Provides covalent bioconjugates for therapeutic/diagnostic target delivery.
Documented Applications
Therapeutic and diagnostic use for target delivery of a compound via the disclosed bioconjugates.
Therapeutic/diagnostic compositions and a therapy/diagnosis kit.
Polyarginine-linked aminoglycoside conjugates with described HIV inhibition potential.
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