WO2017145097A2 - Amino acid and peptide conjugates and conjugation process - Google Patents

Amino acid and peptide conjugates and conjugation process Download PDF

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Publication number
WO2017145097A2
WO2017145097A2 PCT/IB2017/051054 IB2017051054W WO2017145097A2 WO 2017145097 A2 WO2017145097 A2 WO 2017145097A2 IB 2017051054 W IB2017051054 W IB 2017051054W WO 2017145097 A2 WO2017145097 A2 WO 2017145097A2
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Prior art keywords
amino acid
peptide
compound
formula
group
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PCT/IB2017/051054
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English (en)
French (fr)
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WO2017145097A3 (en
Inventor
Margaret Anne Brimble
Geoffrey Martyn Williams
Peter Roderick Dunbar
Daniel VERDON
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Auckland Uniservices Ltd
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Auckland Uniservices Ltd
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Priority claimed from AU2016900701A external-priority patent/AU2016900701A0/en
Priority to AU2017223267A priority Critical patent/AU2017223267B2/en
Priority to EA201891639A priority patent/EA201891639A1/ru
Priority to EP17755925.9A priority patent/EP3419962A4/en
Priority to CA3014515A priority patent/CA3014515A1/en
Priority to US16/076,912 priority patent/US11464853B2/en
Priority to BR112018017174A priority patent/BR112018017174A2/pt
Priority to SG11201807036QA priority patent/SG11201807036QA/en
Application filed by Auckland Uniservices Ltd filed Critical Auckland Uniservices Ltd
Priority to JP2018544904A priority patent/JP7161404B2/ja
Priority to CN201780021838.0A priority patent/CN108884020A/zh
Priority to KR1020187027726A priority patent/KR20180128915A/ko
Publication of WO2017145097A2 publication Critical patent/WO2017145097A2/en
Publication of WO2017145097A3 publication Critical patent/WO2017145097A3/en
Priority to IL261112A priority patent/IL261112A/en
Anticipated expiration legal-status Critical
Priority to AU2021254527A priority patent/AU2021254527A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001104—Epidermal growth factor receptors [EGFR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
    • A61K39/001188—NY-ESO
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/385—Haptens or antigens, bound to carriers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6018—Lipids, e.g. in lipopeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
    • C12N2710/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to amino acid and peptide conjugates, methods for making amino acid and peptide conjugates, conj ugates produced by the methods,
  • compositions comprising the conjugates, methods of eliciting immune responses in a subject a nd methods of vaccinating a subject, uses of the conjugates for the same, and uses of the conj ugates in the manufacture of med icaments for the same.
  • the present invention also relates to methods of making compounds useful in the synthesis of amino acid- and peptide conj ugates of the invention and to such componds.
  • Synthetic peptide vaccines genera lly comprise a synthetic copy of a n immunogenic part of protein antigens. This approach to vaccine development has a number of advantages, including ease of synthesis, avoidance of potentially toxic biological by-products and straightforward characterisation.
  • n adj uva nt designed to activate components of the innate immune system (e.g . Freund's adjuvant) .
  • An alternative strategy in peptide vaccine design is to create self-adjuvanting vaccines in which the peptide epitope of interest is covalently linked to a n appropriate adjuvant.
  • Such self-adj uvanting vaccines may have enhanced antigen uptake, presentation and dendritic cell maturation compared to simple co-formulation of the antigen with an external adjuvant.
  • the present invention broad ly consists in an amino acid- or peptide conjugate compound of the formula (I) :
  • n and w are each independently a n integer from 0 to 7 and v is an integer from 0 to 5,
  • n 1 or 2;
  • Zl and Z2 are each independently selected from the group consisting of -0-, - NR-, -S-, -S(O)-, -SO2-, -C(0)0-, -OC(O)-, -C(0)N R-, -N RC(O)-, -C(0)S-, - SC(O)-, -OC(0)0-, -N RC(0)0-, -OC(0)N R-, and -NRC(0)N R-;
  • Rl, R2, Rx, Ry, R4, R5, R6, and R7 at each instance of m, v, w, a nd n are each independently hyd rogen or Cl-6aliphatic;
  • R, R3, and R8 a re each independently hyd rogen or Cl-6aliphatic;
  • R9 is hydrogen, Cl-6a liphatic, an amino protecting group, L3-C(0)-, or A2;
  • LI and L2 a re each independently selected from is C5-21aliphatic or C4- 20heteroaliphatic;
  • L3 is Cl-21aliphatic or C2-20heteroaliphatic
  • Al is an amino acid, a peptide, OH, OP1, NH2, or NHP2, wherein PI is a carboxyl protecting group, and wherein P2 is a carboxamide protecting group;
  • A2 is an amino acid or a peptide
  • any a liphatic or heteroaliphatic present in any of R, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rx, Ry, LI, L2, and L3 is optionally substituted ;
  • any of the embodiments or preferences described herein may relate to any of the aspects herein alone or in combination with a ny one or more embodiments or preferences described herein, unless stated or the context indicates otherwise.
  • Rl, R2, Rx, Ry, R4, R5, R6, and R7 at each instance of m, v, w, a nd n are each independently hyd rogen, Cl-6a lkyl, C2-6alkenyl, C2-6alkynyl, or C3-6cycloalkyl;
  • R, R3, and R8 a re each independently hydrogen, Cl-6alkyl, C2-6alkenyl, C2- 6alkynyl, or C3-6cycloalkyl ;
  • R9 is hydrogen, Cl-6a lkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, an amino protecting group, L3-C(0), or A2;
  • LI and L2 a re each independently selected from C5-21alkyl, C5-21a lkenyl, C5- 21alkynyl, or C4-20heteroalkyl;
  • L3 is Cl-21alkyl, C5-21alkenyl, C5-21a lkynyl, C3-6cycloalkyl, or C2- 20heteroalkyl;
  • Al is an amino acid, a peptide, OH, OP1, N H2, or NHP2, wherein PI is a carboxyl protecting group, and wherein P2 is a carboxamide protecting group;
  • A2 is an amino acid or a peptide
  • Rl, R2, Rx, Ry, R4, R5, R6, and R7 at each instance of m, v, w, a nd n are each independently hyd rogen, Cl-6a lkyl, C2-6alkenyl, or C3-6cycloa lkyl;
  • R, R3, and R8 a re each independently hydrogen, Cl-6alkyl, C2-6alkenyl, or C3- 6cycloalkyl ;
  • R9 is hydrogen, Cl-6a lkyl, C2-6alkenyl, C3-6cycloalkyl, an amino protecting group, L3-C(0), or A2;
  • LI and L2 a re each independently selected from C5-21alkyl, C5-21alkenyl, or C4- 20heteroalkyl;
  • L3 is Cl-21alkyl, C5-21alkenyl, C3-6cycloa lkyl, or C2-20heteroalkyl ;
  • Al is an amino acid, a peptide, OH, OP1, N H2, or NHP2, wherein PI is a carboxyl protecting group, and wherein P2 is a carboxamide protecting group;
  • A2 is an amino acid or a peptide
  • any a lkyl, a lkenyl, cycloalkyl or heteroalkyl present in any of R, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rx, Ry, LI, L2, and L3 is optiona lly substituted.
  • Rl, R2, Rx, Ry, R4, R5, R6, and R7 at each instance of m, v, w, a nd n are each independently hyd rogen, Cl-6a lkyl, or C3-6cycloalkyl;
  • R, R3, and R8 a re each independently hyd rogen, Cl-6alkyl, or C3-6cycloalkyl;
  • R9 is hydrogen, Cl-6a lkyl, C3-6cycloalkyl, an amino protecting group, L3-C(0), or A2;
  • LI and L2 a re each independently selected from C5-21alkyl, C5-21alkenyl, or C4- 20heteroalkyl;
  • L3 is Cl-21alkyl, C2-21alkenyl, C3-6cycloa lkyl, or C2-20heteroalkyl ;
  • Al is an amino acid, a peptide, OH, OP1, N H2, or NHP2, wherein PI is a carboxyl protecting group, and wherein P2 is a carboxamide protecting group;
  • A2 is an amino acid or a peptide
  • any a lkyl, a lkenyl, cycloalkyl or heteroalkyl present in any of R, Rl, R2, R3, R4, R5, R6, R7, R8, R9, Rx, Ry, LI, L2, and L3 is optiona lly substituted.
  • Rl, R2, Rx, Ry, R4, R5, R6, and R7 at each instance of m, v, w, a nd n are each independently hyd rogen, Cl-6a lkyl, or C3-6cycloalkyl;
  • R, R3, and R8 a re each independently hyd rogen, Cl-6alkyl, or C3-6cycloalkyl;
  • R9 is hydrogen, Cl-6a lkyl, C3-6cycloalkyl, an amino protecting group, L3-C(0), or A2;
  • LI and L2 a re each independently selected from is C5-21alkyl or C4- 20heteroalkyl;
  • L3 is Cl-21alkyl, C3-6cycloalkyl, or C2-20heteroalkyl;
  • Al is an amino acid, a peptide, OH, OP1, N H2, or NHP2, wherein PI is a carboxyl protecting group, and wherein P2 is a carboxamide protecting group;
  • A2 is an amino acid or a peptide
  • Zl and Z2 are each independently selected from the g roup consisting of -C(0)0-, -C(0)NR-, and -C(0)S-.
  • the compound of the formula (I) is a compound of the formula (IA) :
  • v is from 0 to 4, 0 to 3, or 0 to 2, or v is 0 or 1, for example 0.
  • v is from 0 to 3. In exemplary embodiments, v is 0.
  • m and w are each independently from 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.
  • m and w are each independently from 0 to 5.
  • m and w are each independently from 1 to 4.
  • m is from 1 to 6, for example from 2 to 6, 1 to 5, or 2 to 5. In various embodiments, m is from 1 to 5. In various embodiments, m is from 1 to 3. In exemplary embodiments, m is 2.
  • w is 1 or 2. In exemplary embodiments, w is 1.
  • the sum of m and w is from 0 to 6, 0 to 5, 0 to 4, 0 to 3, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3.
  • the sum of m and w is from 2 to 7.
  • the sum of m and w is from 2 to 5.
  • the sum of m and w is 3.
  • v is from 0 to 3; m and w are each independently from 0 to 5; and the sum of m and w is from 2 to 7.
  • v is from 1 or 0; m and w are each independently from 0 to 5; and the sum of m and w is from 2 to 7.
  • v is 1 or 0; m and w are each independently from 1 to 4; and the sum of m and w is from 2 to 7.
  • v is 1 or 0; m and w are each independently from 1 to 4; and the sum of m and w is from 2 to 5.
  • n 1
  • LI and L2 are each independently C5-21aliphatic, for example C9-21alihpatic, Cl l-21aliphatic, or C11-, C13-, C15-, C17-, or C19-aliphatic.
  • LI and L2 are each independently C5-21alkyl.
  • LI and L2 are each independently C9-21alkyl. In yet another embodiment, LI and L2 are each independently CI 1-2 la Iky I.
  • LI and L2 are each independently Cll, C13, C15, C17, or C19alkyl, preferably n-alkyl.
  • LI and L2 are each independently CISalkyl.
  • LI and L2 each independently comprise a linear chain of 9-21 carbon atoms.
  • LI and L2 are each independently linear C15alkyl.
  • L3 is Cl-21alkyl.
  • L3 is methyl or linear C15alkyl.
  • L3 is methyl (that is, R9 is acetyl).
  • the amino protecting group is Boc, Fmoc, Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl) and Dde (l-(4,4-dimethyl-2,6-dioxohexylidene)ethyl).
  • the amino protecting group is Boc or Fmoc.
  • the amino protecting group is Fmoc.
  • the carboxyl protecting group is terf-butyl, benzyl, or allyl.
  • the carboxamide protecting group is Dmcp or Trityl.
  • Rl and R2 at each instance of m are each independently CISalkyl or hydrogen. In various specifically contemplated embodiments, Rl and R2 at each instance of m are each hydrogen. In various embodiments, R3 is Cl-6alkyl or hyd rogen . In various specifically
  • R3 is hyd rogen.
  • R4 and R5 at each instance of w are each independently Cl- 6alkyl or hydrogen, preferably hydrogen. In va rious specifically contemplated embodiments, R4 and R5 at each instance of w are each hydrogen.
  • Rx and Ry at each instance of v are each independently Cl- 6alkyl or hyd rogen. In various specifically contemplated embodiments, Rx and Ry at each instance of v are each hydrogen.
  • R6 a nd R7 at each instance of n are each independently Cl- 6alkyl or hyd rogen. In various specifically contemplated embodiments, R6 and R7 are each hydrogen.
  • R8 is independently Cl-6a lkyl or hydrogen . In exemplary embodiments, R8 is hydrogen.
  • R9 is Cl-6alkyl, hydrogen, a n amino protecting group, L3- C(O), or A2.
  • R9 is hydrogen, an a mino protecting group, L3-C(0), or A2.
  • R8 is hydrogen and R9 is hydrogen, a n amino protecting group, L3-C(0), or A2.
  • R8 a nd R9 are each hydrogen ; or R9 is L3-C(0) or A2.
  • R8 is hydrogen and R9 is L3-C(0).
  • R9 is L3-C(0), wherein L3 is methyl.
  • the compound of formula (I) is a compound of the formula (IF) :
  • n is an integer from 2 to 6, preferably 2;
  • the compound of formula (IF) is a compound of the formula (IF- 1) :
  • the compound of formula (I) is a compound of the formula (IB):
  • k is an integer from 0 to 4.
  • Ra, Rb, and Rc are each independently hydrogen or Cl-6aliphatic.
  • the compound of formula (IB) is a compound of the formula (IC):
  • k is from 0 to 3, 0 to 2, 0 to 1, 1 to 4, 1 to 3, or 1 to 2, or k is 0 or 1.
  • k is 0 to 3. In certain embodiments, k is 0 or 1. In exemplary embodiments, k is 0.
  • Ra, Rb, a nd Rc are each independently hydrogen, Cl-6alkyl, C2-6alkenyl, C2-6a lkynyl, or C3-6cycloalkyl.
  • Ra, Rb, a nd Rc are each independently hydrogen, Cl-6alkyl, C2-6alkenyl, or C3-6cycloalkyl .
  • Ra, Rb, a nd Rc are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl.
  • Ra, Rb, and Rc are each independently selected from hyd rogen or Cl-6alkyl, preferably hydrogen. In exempla ry embodiments, Ra, Rb, and Rc are each hyd rogen.
  • the compound of the formula (I) is a compound of the formula (ID) :
  • the compound is a compound of the formula (ID) wherein LI and L2 are each linear C15alkyl.
  • LI and L2 are each independently CI 1-2 la Iky I ; m is 2; v is 0; w is 1 ; Rl a nd R2 at each instance are each hydrogen ; R3 is hydrogen; and R4 and R5 are each hydrogen.
  • n is 1 ; R6, R7, and R8 are each hydrogen ; and R9 is hydrogen, an amino protecting group, L3-C(0), or A2.
  • n is 1 ; R6, R7, and R8 are each hydrogen ; and R9 is hydrogen, an amino protecting group, or L3-C(0), wherein L3 is linear C15a lkyl or methyl .
  • LI a nd L2 a re each independently Cl l-21alkyl ; m is 2; v is 0; w is 1 ; Rl a nd R2 at each instance are each hydrogen ; R3 is hyd rogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, a nd R8 are each hydrogen; and R9 is hydrogen, an amino protecting group, or L3-C(0), wherein L3 is linear C15alkyl or methyl .
  • the compound of formula (I) has the formula (IE) :
  • the compound of formula (I) has the formula (IEE):
  • the compound of formula (I) has the formula (IE-1):
  • the compound of formula (I) has the formula (IEE-1) :
  • the compound of formula (I) has the formula (IE-2):
  • the compound of formula (I) has the formula (IEE-2) :
  • the compound of formula (I) has the formula (IEE-3) :
  • the compound of formula (I) has the formula (IEE-4) :
  • the amino acid of the amino acid- or peptide conjugate to which the lipid moieties are conjugated is a cysteine resid ue.
  • the moieties Ll-Zl- and L2-Z2- may be fatty acid g roups, for example fatty acid esters.
  • the moieties may be saturated or unsaturated fatty acid esters.
  • the fatty acid is saturated .
  • the fatty acid is a C4-22 fatty acid . In some embodiments, the fatty acid is a C6-22 fatty acid. In certain embodiments, the fatty acid is a ClO-22 fatty acid. In certa in specifically contemplated embodiments, the fatty acid is a C12-22 fatty acid . In various exempla ry embodiments, the fatty acid is a C12, C14, C16, C18, or C20 fatty acid .
  • the fatty acid is la uric acid, myristic acid, palmitic acid, stea ric acid, arachic acid, palmitoleic acid, oleic acid, elaidic acid, linoleic acid, a-linolenic acid, and a rachidonic acid .
  • the fatty acid is lauric acid, myristic acid, palmitic acid, or stearic acid .
  • the fatty acid is palmitic acid (and the moieties Ll- Zl- a nd L2-Z2-are each palmitoyl groups).
  • the compound of formula (I) is an amino acid-conjugate.
  • Al is OH, OPl, N H2, or NHP2 and/or R9 is hydrogen, Cl-6alkyl, C3-6cycloalkyl, an amino protecting group, or L3-C(0).
  • Al is OPl or OH a nd/or R9 is hydrogen, an amino protecting group or L3-C(0) .
  • Al is OH, OPl, N H2, or NHP2 a nd R9 is hydrogen, Cl-6a lkyl, C3-6cycloalkyl, an amino protecting group, or L3-C(0).
  • Al is OH, or OPl
  • R9 is hydrogen, an amino protecting group, or L3-C(0).
  • R9 is hydrogen, an amino protecting group or L3-C(0). In some embodiments, R9 is hydrogen or L3-C(0).
  • the compound of formula (I) is a peptide conjugate.
  • Al and/or A2 is an amino acid or a peptide.
  • Al and/or A2 is a peptide.
  • Al and/or A2 is a peptide comprising an epitope.
  • Al and/or A2 is a peptide comprising a peptide epitope.
  • Al a nd/or A2 is a peptide, wherein the peptide comprises a peptide epitope.
  • Aland/or A2 is a peptide substituted with a n epitope.
  • the epitope is bound to the peptide via a linker group.
  • Al is a peptide.
  • Al is a peptide and R9 is not A2 (that is, R9 is not a n amino acid or a peptide).
  • the peptide comprises an epitope.
  • the epitope is a peptide epitope.
  • the epitope is coupled or bound via a linker group.
  • the amino acid of the peptide conjugate to which the lipid moieties are conjugated is an N-terminal amino acid residue.
  • Al is serine or a peptide comprising serine as the first N- termina l amino acid residue.
  • Al is a peptide comprising serine as the first N-termina l amino acid residue.
  • the peptide conjugate comprises one or more solubilising groups.
  • the solubilising group comprises an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • the solubilising group is an amino acid sequence comprising a sequence of two or more consecutive hydrophilic amino acid residues in the peptide chain.
  • the two or more hydrophilic amino acid residues are adjacent to the serine residue.
  • Al a nd/or A2 is a peptide comprising a solubilising group.
  • Al and/or A2 is a peptide comprising a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • Al is a peptide comprising a solubi lisi ng group comprising an amino acid seq uence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • Al is a peptide comprising serine as the first N-termina l amino acid residue and a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain adjacent to the serine.
  • the compound comprises a linker or one or more amino acids thereof.
  • the peptide comprises a linker or one or more amino acids thereof.
  • the peptide comprises a peptide epitope bound via a linker to the amino acid to which the lipid moieties are bound .
  • the peptide comprises two or more epitopes.
  • the peptide comprises a peptide a ntigen.
  • the linker is an amino acid sequence from about 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 amino acids in length.
  • the compound of formula (I) comprises 3 or more, 4 or more, or 5 or more contiguous a mino acids.
  • the peptide conjugate is a lipopeptide.
  • the compound of formula (I) is a self adjuvanting peptide.
  • Al a nd/or A2 are each independently a peptide comprising from about 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • Al and A2 are each independently a peptide comprising from about 8 to 60 amino acids.
  • Al a nd/or A2 are each independently a peptide comprising from about 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • Al a nd/or A2 are each independently a peptide comprising from about 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • Al and/or A2 are each independently a peptide, wherein the peptide comprises 8 to 60 amino acids.
  • Al and/or A2 are each independently a peptide comprising or substituted with a peptide epitope, wherein the peptide epitope compises from 8 to 60 amino acids.
  • Suitable peptide epitopes include without limitation those described in WO 2016/103192 filed 22 December 2015, the entirety of which is incorporated herein by reference.
  • the peptide comprises, consists essentially of, or consists of one or more EBV LM P2 epitopes.
  • the one or more EBV LM P2 epitopes a re MHCI epitopes.
  • the peptide comprises one or more EBV LM P2 epitopes selected from the group consisting of a ny one of SEQ ID NOs 76 - 101.
  • the peptide comprises a peptide comprising or consisting of 8 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises a peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75. In va rious embodiments, the peptide comprises a peptide comprising or consisting of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprising or consisting of 20 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises a recombina nt peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the recombinant peptide comprises or consists of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprises or consists of 20 or more contig uous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises, consists of, or consists essentially of a n amino acid seq uence selected from the group consisting of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises, consists of, or consists essentia lly of an amino acid seq uence selected from the group consisting of
  • Xaa iXaa 2 Xaa 3 DRHSDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 2], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic a mino acids,
  • Xaa iXaa 2 DRHSDYQPLGTQDQSLYLGLQHDGN DGL [SEQ ID NO: 3], wherein Xaa l is absent or is S or a hyd rophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4SLYLGLQHDGN DGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 6], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa 2 Xaa 3 SLYLGLQHDGN DGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 7], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic a mino acids,
  • Xaa iXaa 2 SLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 8], wherein Xaa l is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa 2 Xaa 3 SDYQPLGTQDQSLYLGLQHDGN DGL [SEQ ID NO: 12], wherein Xaai is absent or is S or a hyd rophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 SDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 13], wherein Xaai is absent or is S or a hyd rophilic amino acid, a nd Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa3Xaa4DRHSDYQPLGTQDQSLYLGLQHDGN DGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO : 16], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 DRHSDYQPLGTQDQSLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 17], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 DRHSDYQPLGTQDQSLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 18], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO: 21], wherein Xaai is absent or is S or a hyd rophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO: 22], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic a mino acids,
  • Xaa iXaa 2 LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO : 23], wherein Xaa i is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 26], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hyd rophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, a nd Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 27], wherein Xaai is absent or is S or a hyd rophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 28], wherein Xaai is absent or is S or a hyd rophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids, (cc) 8 or more contiguous amino acid residues from the seq uence
  • Xaa iXaa2Xaa 3 Xaa4LM LLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 31 ], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic a mino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 LMLLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 32], wherein Xaa i is absent or is S or a hyd rophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 LMLLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 33], wherein Xaa i is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa 1Xaa2Xaa3Xaa4LLICSSCSSCPLSKILLARLFLYALAL.LL.LA [SEQ ID NO: 36], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic a mino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa 2 LLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO : 38], wherein Xaa i is absent or is S or a hyd rophilic amino acid, a nd Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa 2 LNLTTMFLLM LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLASALIAGGSI [SEQ ID NO :43], wherein Xaa i is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4FLLMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLASA [SEQ ID NO:46], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hyd rophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa 2 FLLMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLASA [SEQ ID NO:48], wherein Xaai is absent or is S or a hyd rophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4LQGIYVLVMLVLLILAYRRRWRRLTVCGGIMFLACVLVLIVDAVLQLSPLL [SEQ ID NO: 51 ], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 LQGIYVLVMLVLLILAYRRRWRRLTVCGGIM FLACVLVLIVDAVLQLSPLL [SEQ ID NO : 52], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 SGN RTYGPVFM(C)(S)LGGLLTMVAGAVWLTVMSNTLLSAWILTAGFLIFLIG FA [SEQ ID NO: 57], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 SGN RTYGPVFM(C)(S)LGGLLTMVAGAVWLTVMSNTLLSAWILTAGFLIFLIGFA [SEQ ID NO : 58], wherein Xaa i is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa3Xaa4SN EEPPPPYEDPYWGNGDRHSDYQPLGTQDQSLYLGLQHDGNDGLPP [SEQ ID NO : 61 ], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa 2 SNEEPPPPYEDPYWGNGDRHSDYQPLGTQDQSLYLGLQHDGNDGLPP [SEQ ID NO: 63], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 GNDGLPPPPYSPRDDSSQHIYEEAGRGSMNPVCLPVIVAPYLFWLAAIAAS [SEQ ID NO : 67], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 GN DGLPPPPYSPRDDSSQHIYEEAGRGSMN PVCLPVIVAPYLFWLAAIAAS [SEQ ID NO: 68], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 Xaa4AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID N0 : 71 ], wherein Xaa i is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • Xaa iXaa2Xaa 3 AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID NO: 72], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • Xaa iXaa 2 AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID NO: 73], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • LGTQDQSLY [SEQ ID NO: 81 ]
  • LIVDAVLQL [SEQ ID NO: 99]
  • LTAGFLIFL [SEQ ID NO: 100]
  • the peptide comprises one or more epitopes derived from Latent Membrane Protein 2 (LMP2), for example, from full-length EBV LM P2 (amino acids 1-497).
  • LMP2 Latent Membrane Protein 2
  • the peptide comprises, consists essentia lly of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentia lly of, or consists of an amino acid sequence selected from the group consisting of 12 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentia lly of, or consists of an amino acid sequence selected from the group consisting of 15 or more, 18 or more, 20 or more, or 25 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentially of, or consists of a n amino acid seq uence selected from the group consisting of any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentia lly of, or consists of an amino acid sequence selected from the group consisting of 15 or more, 18 or more, 20 or more, or 25 or more contiguous amino acid residues from any one of SEQ ID NOs: 1 to 75.
  • the peptide comprises, consists essentially of, or consists of a n amino acid seq uence selected from the group consisting of a ny one of SEQ ID NOs: 1 to 75.
  • the peptide comprises an amino acid sequence selected from the group consisting of a ny one of SEQ ID NOs: 76 to 101. In one example, the peptide comprises a n amino acid sequence selected from the group consisting of a ny one of SEQ ID NOs: 76 to 93.
  • the peptide comprises an amino acid sequence selected from the group consisting of any two or more of SEQ ID NOs : 76 to 101. In one example, the peptide comprises an amino acid sequence selected from the g roup consisting of any two or more of SEQ ID NOs: 76 to 93.
  • the peptide comprises, consists of, or consists essentially of a n amino acid seq uence selected from the group consisting of
  • Xaai is absent or is S
  • Xaa2 is absent or is a hydrophilic amino acid
  • Xaa3 is absent or is a hydrophilic amino acid
  • Xaa4 is absent or is one or more hyd rophilic amino acids
  • XaaiXaa 2 Xaa 3 GARGPESRLLEFYLAMPFATPM EAELARRSLAQDAPPL [SEQ ID NO: 103], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa2GARGPESRLLEFYLAMPFATPMEAELARRSLAQDAPPL [SEQ ID NO : 104], wherein Xaai is absent or is S, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa2Xaa 3 Xaa4VPGVLLKEFTVSGNILTIRLTAADHR [SEQ ID NO: 109], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hyd rophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 VPGVLLKEFTVSGNILTIRLTAADHR [SEQ ID NO: 110], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 VPGVLLKEFTVSGNILTIRLTAADHR [SEQ ID NO: l l l], wherein Xaai is absent or is S, and Xaa 2 is absent or is from one to four hyd rophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa4LQQLSLLMWITQCFLPVFLAQPPSGQRR [SEQ ID NO: 115], wherein Xaai is absent or is S, Xaa 2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids
  • XaaiXaa 2 Xaa 3 LQQLSLLMWITQCFLPVFLAQPPSGQRR [SEQ ID NO: 116], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 LQQLSLLMWITQCFLPVFLAQPPSGQRR [SEQ ID NO: 117], wherein Xaai is absent or is S, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • the peptide epitope is derived from NY-ESO-1.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous amino acid residues from any one of SEQ ID NO: 106, 107, 108, 113, 114, 119, 120, a nd 121.
  • the peptide comprises, consists essentially of, or consists of a n amino acid seq uence selected from the group consisting of any one of SEQ ID NO: 106, 107, 108, 113, 114, 119, 120, and 121.
  • the peptide comprises, consists essentially of, or consists of a n amino acid seq uence selected from the group consisting of any one of SEQ ID NO: 106, 113, and 119. In one embodiment, the peptide comprises, consists essentially of, or consists of a n amino acid seq uence selected from the group consisting of any one of SEQ ID NO: 105, 112, and 118.
  • the peptide comprises, consists essentially of, or consists of one or more ovalbumin protein epitopes.
  • the one or more ovalbumin protein are MHCI epitopes.
  • the one or more ovalbumin protein are MHCII epitopes.
  • the peptide comprises, consists essentially of, or consists of:
  • XaaiXaa2Xaa3Xaa4 KISQAVHAAHAEINEAGRESIIN FEKLTEWT [SEQ ID NO: 124], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, Xaa3 is absent or is a hydrophilic amino acid, and Xaa4 is absent or is one or more hydrophilic amino acids
  • KISQAVHAAHAEIN EAGRESIINFEKLTEWT [SEQ ID NO : 125], wherein Xaai is absent or is S, Xaa2 is absent or is a hydrophilic amino acid, and Xaa3 is absent or is from one to ten hyd rophilic amino acids,
  • KISQAVHAAHAEIN EAGRESIINFEKLTEWT [SEQ ID NO : 126], wherein Xaai is absent or is S, and Xaa2 is absent or is from one to four hydrophilic amino acids,
  • the peptide comprises one or more ovalbumin protein epitopes selected from the group consisting of any one of SEQ ID NOs 124 - 130. In various embodiments, the peptide comprises a peptide comprising or consisting of 8 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 124 -
  • the peptide comprises, consists of, or consists essentially of an amino acid sequence selected from the group consisting of any one of SEQ ID NOs 124 -
  • the peptide conjugate comprises two or more epitopes, such as two or more peptide epitopes.
  • the peptide conjugate comprises an antigenic peptide.
  • the peptide is a synthetic peptide.
  • the compound of formula (I) is an isolated compound of formula (I).
  • the compound of formula (I) is a pure, purified or substantially pure compound of formula (I).
  • the present invention broadly consists in a method of making a compound of the formula (XV), the method comprising reacting
  • X10 is L1-Z1-, -OH, -SH, -NHR, HN RC(0)0-, P10-O-, P11-S-, P12-N R-, or P12-N RC(0)0-;
  • Xl l is X10 or -OH, -SH, -N HR, or HNRC(0)0- when X10 is P10-O-, P11-S-, P12- NR-, or P12-NRC(0)0- and said conditions are effective to remove P10, Pl l, or P12;
  • P10, Pl l, and P12 are each independently a protecting group
  • n is an integer from 2 to 6;
  • n, LI, Zl, R, Rl, R2, R3, R4, R5, R6, R7, R8, R9, and Al are as defined in the compound of formula (I) or any embodiment thereof; or a salt or solvate thereof.
  • n is from 2 to 5, 2 to 4, or 2 to 3. In exemplary embodiments, m is 2.
  • X10 is Ll-Zl- or -OH, -SH, -NHR, P10-O-, P11-S-, or P12- NR-; a nd Xl l is X10 or -OH, -SH, or -NHR.
  • X10 is L1-Z1-, -OH, or P10-O-; and Xl l is X10 or -OH .
  • X10 is L1-C(0)0-, OH, or P10-O-; and Xl l is L1-C(0)0-, P10-O-, or OH .
  • X10 is L1-C(0)0- or P10-O-; and Xl l is L1-C(0)0-, P10-O-, or OH .
  • X10 is P10-O-; a nd Xl l is PIO-O- or OH .
  • R9 is not hydrogen and/or Al is not OH .
  • the amino acid-comprising conj ugation partner is a peptide containing conjugation partner comprising 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, or 3 or less amino acid residues.
  • the C-terminus of the amino acid comprising conj ugation partner is protected with a carboxyl protecting group or a carboxamide protecting group and/or the Na-amino group of the amino acid comprising conjugation partner is protected with an amino protecting group.
  • R9 is an amino protecting group.
  • Al is OP1 or NHP2. In certa in embodiments, Al is OP1.
  • R9 is an amino protecting group and Al is OP1.
  • the method comprises reacting the epoxide and amino acid- comprising conj ugation partner in the presence of an acid, for example a strong acid .
  • the acid comprises hydrochloric acid, sulfuric acid, or a mixture thereof.
  • the acid comprises a lewis acid, for example BF3.
  • the method comprises reacting the epoxide and amino acid- comprising conjugation partner under neutral conditions.
  • the neutral conditions comprise a protic solvent, such as an alcohol, for example ethanol.
  • the method comprises reacting the epoxide and amino acid- comprising conj ugation partner in the presence of a base, for example a mild base.
  • the base is an organic a mine, for example triethylamine.
  • the method comprises providing the epoxide by reacting a n alkene of the formula (XVII) :
  • the oxida nt is a peroxide, such as an organic peroxide, for example m-chloro peroxybenzoic acid, or a n organic N-oxide, for example pyridine N- oxide.
  • the method comprises providing the epoxide by reacting a n compound of the formula (XVII-A) a leaving group:
  • the compound of formula (XVII-A) is prepared from L-aspartic acid .
  • the method further comprises providing a single stereoisomer or a stereoisomerically enriched mixture of the epoxide of formula (XVI).
  • providing the single stereoisomer or a stereoisomerically enriched mixture of the epoxide of formula (XVI) comprises resolving a racemic mixture of the epoxide.
  • the method comprises provid ing a single stereoisomer or a stereoisomerically enriched mixture of the compound of formula (XVII-A).
  • the method comprises converting the compound of formula (XV) to a n amino acid- or peptide conj ugate of the formula (IF) or a pharmaceutica lly acceptable salt or solvate thereof of the present invention by one or more additional synthetic steps:
  • the method comprises converting the compound of formula (XV) to a n amino acid- or peptide conj ugate of the formula (IF-1) or a pharmaceutically acceptable salt or solvate thereof of the present invention by one or more additional synthetic steps:
  • the one or more synthetic steps comprises converting the hydroxyl group bound to the carbon to which R3 is attached to L2-Z2-.
  • the one or more synthetic steps comprises acylating the compound of formula (XV) so as to replace the hydrogen atom of the hydroxyl group bound to the carbon to which R3 is attached with L2-C(0)-.
  • Xl l is PIO-O- or OH; and the one or more synthetic steps comprise acylating the compound of formula (XV) so as to replace P10 or the hydrogen atom of the hydroxyl group of Xl l with Ll-C(O)-; and/or acylating the compound of formula (XV) so as to replace the hydrogen atom of the hydroxyl group bound to the carbon to which R3 is attached with L2-C(0)-.
  • the present invention broadly consists in a compound of the formula (XV) :
  • Xll is L1-Z1-, -OH, -SH, -NHR, HNRC(0)0-, P10-O-, P11-S-, P12-NR-, or P12-NRC(0)0-;
  • P10, Pll, and P12 are each independently a protecting group
  • n is an integer from 2 to 6;
  • n, LI, Zl, R, Rl, R2, R3, R4, R5, R6, R7, R8, R9, and Al are as defined in the compound of formula (I) or any embodiment thereof; or a salt or solvate thereof.
  • the present invention broadly consists in the use of a compound of the formula (XV) or (XVI) in the synthesis of an amino acid- or peptide-conj ugate of the formula (IF) of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention broadly consists in a method of making a compound of the formula (XX), the method comprising reacting
  • Rm and Rn are each independently hydrogen, Cl-6alkyl, aryl, or heteroaryl; LG is a leaving group;
  • n and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5,
  • n, Rx, Ry, Rl, R2, R3, R4, R5, R6, R7, R8, R9, and Al are as defined in the compound of formula (I) or any embodiment thereof; or a salt or solvate thereof.
  • Rm and Rn are each independently selected from hydrogen, Cl-6alkyl, or aryl.
  • Rm is hydrogen, Cl-6alkyl, or aryl; and Rn is Cl-6alkyl or aryl.
  • the leaving group is a halo (for example chloro, bromo, or iodo) or sulfonate (for example a tosylate or mesylate).
  • halo for example chloro, bromo, or iodo
  • sulfonate for example a tosylate or mesylate
  • m and v are such that the compound comprises a 5-7- membered cyclic acetal.
  • the cyclic aceta l is a 6-membered cyclic acetal.
  • the cyclic acetal is a 5-membered cyclic acetal and w is a n integer greater than 1.
  • m is 2 and v is 1.
  • R9 is not hydrogen and/or Al is not OH .
  • the amino acid-comprising conj ugation partner is a peptide containing conjugation partner comprising 15 or less, 14 or less, 13 or less, 12 or less, 11 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, or 3 or less amino acid residues.
  • the C-terminus of the amino acid comprising conj ugation partner is protected with a carboxyl protecting group or a carboxamide protecting group and/or the Na-amino group of the amino acid comprising conjugation partner is protected with an amino protecting group.
  • R9 is an amino protecting group.
  • Al is OP1 or NHP2. In certa in embodiments, Al is OP1.
  • R9 is an amino protecting group and Al is OP1.
  • the method comprises reacting the compound of formula (XXI) and the amino acid-comprising conjugation partner of formula (III) in the presene of a base.
  • the base comprises an orga nic amine, for exa mple
  • the cyclic acetal of formula (XXI) is provided in the form of a single stereoisomer or a stereoisomerically enriched mixture.
  • the method comprises converting the compound of formula (XX) to a n amino acid- or peptide conj ugate of the formula (I) or a pharmaceutically acceptable salt or solvate thereof of the present invention by one or more additional synthetic steps:
  • the method comprises converting the compound of formula (XX) to a n amino acid- or peptide conj ugate of the formula (IA) or a pharmaceutically acceptable salt or solvate thereof of the present invention by one or more synthetic steps:
  • the one or more synthetic steps comprises removing the acetal in the compound of formul of the formula (XXIII-1) :
  • the method comprises removing the acetal in the compound of formula (XX) to provide a compound of the formula (XXIII-2) or (XXIII-3):
  • the one or more synthetic steps comprise converting the hydroxyl group bound to the carbon to which Rl and R2 are attached in the compound of formula (XXIII-1) to L1-Z1-, and/or converting the hydroxyl group bound to the carbon to which Rx and Ry are attached to L2-Z2.
  • the one or more synthetic steps comprise
  • converting said hydroxyl group to Ll-Zl- or L2-Z2- comprises acylating so as to replace the hydrogen atom of the hydroxyl group with Ll-C(0)-or L2- C(O)-.
  • the present invention broadly consists in a compound of the formula (XX) : wherein :
  • Rm and Rn a re each independently hydrogen, Cl-6alkyl, aryl, or heteroaryl; m and w are each independently a n integer from 0 to 7 and v is an integer from 0 to 5,
  • the present invention broadly consists in the use of a compound of the formula (XX) or (XXI) in the synthesis of a n amino acid- or peptide-conj ugate of the formula (IA) of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention broadly consists in a method of making an amino acid- or peptide conj ugate of the formula (I) or a pharmaceutically acceptable salt or solvate thereof of the present invention, the method comprising reacting
  • a first lipid-containing conj ugation partner comprising a carbon-carbon double bond
  • lipid-containing conj ugation partner comprising a carbon-carbon double bond
  • conjugation pa rtner comprising a thiol
  • the amino acid-comprising conjuation partner is a peptide- containing conjugation partner, a nd the lipid-containing conjugation partners are coupled to the peptide of the peptide-containing conjugation partner.
  • the lipid-containing conjugation partners are conjugated to the or an amino acid of the amino acid-comprising conjugation pa rtner or the peptide of the peptide-containing conjugation partner.
  • the lipid-containing conjugation pa rtners are conjugated to the or a n amino acid of the amino acid-comprising conj ugation partner.
  • the present invention broad ly consists in a method of making a peptide conj ugate of formula (I) or a pharmaceutically acceptable salt or solvate thereof of the present invention, the method comprising reacting
  • a first lipid-containing conj ugation partner comprising a carbon-carbon double bond
  • lipid-containing conj ugation partner comprising a carbon-carbon double bond
  • the conjugate is a lipopeptide, such that the method is for making a lipopeptide.
  • the first and second lipid-conta ining conj ugation partners have the same structure (that is, the first a nd second lipid-conta ining conj ugation pa rtners are identical).
  • the method comprises conjugating the sulfur atom of the thiol to a carbon atom of the carbon-carbon double bond of the first lipid containing conjugation partner and then conjugating a carbon atom from the carbon-carbon double bond to which the thiol is conjugated to a carbon atom of the carbon-carbon double bond of the second lipid-containing conjugation partner.
  • the first lipid-containing conjugation partner is a compound of the formula (IIA):
  • the second lipid-containing conjugation partner is a compound of the formula
  • amino acid-comprising conjugation partner comprises a structure of the formula (III):
  • Ra, Rb, Rc, LI, L2, Zl, Z2, Rl, R2, Rx, Ry, R3, R4, R5, R6, R7, R8, R9, Al, k, v, and n are as defined in the compound of formula (I) or any embodiment thereof.
  • the amino acid- or peptide conjugate is a compound of the formula (IB):
  • the lipid containing conjugation partners are in stoichiometric excess to the amino acid-comprising conjugation partner.
  • the mole ratio of the lipid containing conjugation partners (combined) to amino acid-comprising conjugation partner is at least 7: 1.
  • the first lipid-containing conjugation partner is a compound of the formula (IIA-1):
  • the second lipid-containing conjugation partner is a compound of the formula
  • amino acid-comprising conjugation partner comprises a structure of the formula (III):
  • the conjugate is a compound of the formula (IC):
  • LI is Cl l-21alkyl
  • k is 0-3, preferably 0
  • Ra, Rb, and Rc are each hydrogen.
  • L2 is CI 1-2 la Iky I; v is 0-3, preferably 0; and R3, R4, and R5 are each hydrogen.
  • n is 1 ; R6, R7, and R8 are each hydrogen ; and R9 is hydrogen, an amino protecting group, L3-C(0), or A2.
  • n is 1 ; R6, R7, and R8 are each hydrogen ; and R9 is hydrogen, an amino protecting group, or L3-C(0), wherein L3 is linear C15a lkyl or methyl .
  • the compounds of formula (IIA) a nd (IIB) a re each vinyl pa Imitate.
  • the amino-acid comprising conj ugation partner is cysteine, a protected cysteine (including Na-amine a nd/or carboxyl protected cysteine), or a peptide comprising a cysteine residue (including an ⁇ -amine or carboxyl protected cysteine residue), for example, a n N-terminal cysteine residue (including an ⁇ -amine protected cysteine residue).
  • the method comprises reacting vinyl pa lmitate and an Na-amino protected cysteine, such as Fmoc-Cys-OH, Boc-Cys-OH, Fmoc-Cys-OPl, or Boc-Cys-OPl .
  • an Na-amino protected cysteine such as Fmoc-Cys-OH, Boc-Cys-OH, Fmoc-Cys-OPl, or Boc-Cys-OPl .
  • the carboxyl group of the Na-amino protected cysteine is protected .
  • the conditions effective to conjugate the lipid-containing conj ugation partners to the amino acid-comprising conjugation pa rtner comprises the generation of one or more free radicals. In one embodiment, the conditions effective to conj ugate the lipid-containing conj ugation partners to the peptide-conta ining conjugation partner comprises the generation of one or more free radicals.
  • the generation of one or more free radica ls is initiated therma lly and/or photochemica lly.
  • the generation of one or more free radicals is initiated by the thermal and/or photochemica l degradation of a free radical initiator.
  • the generation of one or more free radicals is initiated by the thermal degradation of a therma l initiator or the photochemical degradation of a photochemical initiator.
  • thermal degradation of the free radica l initiator comprises heating the reaction mixture at a suitable temperature.
  • the reaction mixture is heated at a temperature is from about 40 °C to about 200 °C, from about 50 °C to about 180 °C, from about 60 °C to about 150 °C, from about 65 °C to about 120 °C, from about 70 °C to about 115 °C, from about 75 °C to about 110 °C, or from about 80 °C to about 100 °C.
  • the reaction mixture is heated at a temperature of at least about 40 °C, at least about 50 °C, at least about 60 °C, or at least about 65 °C. In one specifically contemplated embodiment, the reaction mixture is heated at a temperature of about 90 °C.
  • photochemical degradation of the free radical initiator comprises irrad iation with ultraviolet light, preferably having a frequency compatiable with the side chains of naturally occurring amino acids.
  • the ultraviolet light has a wavelength of about 365 nm.
  • photochemical degradation of the free radical initiator is carried out at about ambient temperature.
  • the thermal initiator is 2,2'- azobisisobutyronitrile (AIBN) .
  • AIBN 2,2'- azobisisobutyronitrile
  • the photoinitiator is 2,2-dimethoxy-2-phenylacetophenone (DMPA).
  • the reaction is carried out in a liquid med ium.
  • the liquid medium comprises a solvent.
  • the solvent is selected from the group consisting of N-methylpyrrolidone (N MP), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylformamide (DMF), dichloromethane (DCM), 1,2-dichloroethane, and mixtures thereof.
  • N MP N-methylpyrrolidone
  • DMSO dimethylsulfoxide
  • DMF ⁇ , ⁇ -dimethylformamide
  • DCM dichloromethane
  • 1,2-dichloroethane 1,2-dichloroethane, and mixtures thereof.
  • the solvent comprises NMP, DMF, DMSO, or a mixture thereof.
  • the solvent comprises DMSO or NMP. In exemplary embod iments, the solvent comprises NMP.
  • the reaction is carried out in the presence of one or more additives that inhibit the formation of by-prod ucts and/or that improve the yield of or conversion to the desired prod uct compound of formula (I).
  • the one or more additive is an extra neous thiol, an acid, an orga nosilane, or a combination of a ny two or more thereof.
  • the extraneous or exogenous thiol is selected from the group consisting of reduced glutathione (GSH), 2,2'-(ethylened ioxy)diethanethiol (DODT), 1,4-dithiothreitol (DTT), protein, and sterically hindered thiols.
  • GSH reduced glutathione
  • DODT 2,2'-(ethylened ioxy)diethanethiol
  • DTT 1,4-dithiothreitol
  • protein protein
  • sterically hindered thiols sterically hindered thiols.
  • the extraneous or exogenous thiol is DTT.
  • the extraneous or exogenous thiol is a sterically hindered thiol, for example tert-butyl mercaptan.
  • the acid additive is a strong inorganic or organic acid .
  • the acid is a strong organic acid .
  • the acid is TFA.
  • the organosilane is a tria lkylsilane, for example TIPS.
  • the one or more additive is selected from the group consisting of TFA, terf-butyl mercapta n, TIPS, and combinations of any two or more thereof.
  • the one or more additive is a combination of a n acid and an extraneous thiol, for example TFA and terf-butyl mercaptan.
  • the one or more add itive is a combination of an acid and an orga nosilane, for example TFA a nd TIPS.
  • the one or more add itive is a combination of an extraneous thiol and a n organosilane, and optionally a n acid, for example a combination of t-BuSH and TIPS, and TFA.
  • the reaction is carried out for a period of time from about 5 minutes to about 48 h, 5 minutes to about 24 h, from about 5 minutes to about 12 hours, from about 5 minutes to about 6 hours, from about 5 minutes to about 3 hours, 5 minutes to 2 hours, or form about 5 minutes to about 1 hour.
  • the reaction is carried out for a period of time from about 5 minutes to about 48 h, 5 minutes to about 24 h, from about 5 minutes to about 12 hours, from about 5 minutes to about 6 hours, from about 5 minutes to about 3 hours, 5 minutes to 2 hours, or form about 5 minutes to about 1 hour.
  • the reaction is carried out for a period of time from about 5 minutes to about 1 h. In some embodiments, the reaction is carried out until one of the conj ugation partners is at least about 70%, 80%, 90%, 95%, 97%, 99%, or 100% consumed .
  • the reaction is carried out under substantia lly oxygen free conditions.
  • the amino acid-comprising conj ugation partner is a peptide- containing conjugation partner.
  • the amino acid-comprising conjugation partner comprises an epitope. In one embodiment, the peptide-containing conj ugation partner comprises an epitope, such as a peptide epitope. In one embodiment, the amino acid-comprising conjugation partner comprises two or more epitopes. In one embodiment, the peptide-containing conjugation partner comprises two or more epitopes.
  • the amino acid-comprising conjugation partner consists of a peptide.
  • the amino acid-comprising conjugation partner consists of a peptide comprising a peptide epitope. In one embodiment, the peptide-containing conjugation partner consists of a peptide. In one embodiment, the peptide-containing conjugation partner consists of a peptide comprising a peptide epitope.
  • the amino acid-comprising conj ugation partner comprises an epitope bound to the or an amino acid of the conjugation partner.
  • the peptide-containing conj ugation partner comprises an epitope bound to the peptide of the peptide containing conjugation partner.
  • the epitope is bound to the peptide via linker group.
  • the amino acid-comprising conj ugation partner comprises a peptide epitope bound to the or an amino acid of the conj ugation partner via a linker group.
  • the peptide-containing conj ugation partner comprises a peptide epitope bound to the peptide via a linker group.
  • the amino acid-comprising conj ugation partner and/or the peptide-containing conjugation partner comprises an antigenic peptide.
  • the amino acid-comprising conjugation partner a nd/or peptide conjugate comprises a synthetic peptide.
  • the synthetic peptide is a peptide prepared by a method comprising solid phase peptide synthesis (SPPS).
  • the method comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate to an amino acid or an amino acid of a peptide to provide a peptide conjugate.
  • the method comprises coupling the amino acid of the amino acid conjugate to an amino acid or an amino acid of a peptide to provide a peptide conjugate.
  • the peptide comprises an epitope.
  • the epitope is a peptide epitope.
  • the method further comprises coupling the amino acid of the amino acid conjugate to an amino acid or a peptide to provide a peptide conjugate.
  • coupling a peptide comprises individually coupling one or more amino acids and/or one or more peptides.
  • the method further comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conj ugate to an a mino acid or a peptide so as to provide a peptide conjugate comprising a linker g roup or one or more amino acids thereof.
  • the method further comprises coupling an amino acid of the peptide conjugate comprising a linker group or one or more amino acids thereof to a n amino acid or a peptide so as to provide a peptide conjugate comprising a peptide epitope bound to the amino acid to which lipid moieties are conjugated via a linker group.
  • the amino acid of the peptide conjugate to which the lipid moeities are conjugated is an N-terminal amino acid resid ue.
  • the method further comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conj ugate to an a mino acid or a peptide so as to provide a peptide conjugate comprising a peptide epitope.
  • the method further comprises coupling an epitope to the amino acid of the amino acid conj ugate or a n amino acid of the peptide conj ugate.
  • the method further comprises coupling a peptide epitope to the amino acid of the amino acid conjugate or a n amino acid of the peptide conj ugate.
  • the epitope is coupled or bound via a linker group.
  • the method further comprises coupling an epitope to the peptide of the peptide conjugate.
  • the method further comprises coupling a peptide epitope to the peptide of the peptide conjugate.
  • the epitope is bound to the peptide via a linker group.
  • the amino acid-comprising conjugation partner consists of a n amino acid, for example cysteine (including Na-amino and/or C-terminus protected cysteines).
  • the C-terminus of the amino acid comprising conj ugation partner is protected with a protecting group a nd/or the Na-amino group of the amino acid comprising conjugation partner is protected with a protecting group.
  • the carboxyl group of the C-terminus of the a mino acid is protected with a carboxyl protecting group or a carboxamide protecting group and/or the Na-amino group of the amino acid is protected with an amino protecting group.
  • the carboxyl group of the C-terminus of the a mino acid is protected with a carboxyl protecting group and/or the ⁇ -amino group of the amino acid is protected with an amino protecting group.
  • the carboxyl group of the C-terminus of the peptide is protected with a carboxyl protecting group and/or the ⁇ -amino group of the peptide is protected with an amino protecting group.
  • the amino acid residue comprising the thiol is a terminal amino acid residue. In some embodiments, the amino acid resid ue comprising the thiol is an N- termina l residue.
  • Al and/or R9 is a group other than an amino acid or a peptide
  • the method comprises coupling an amino acid or a peptide so as to replace Al and/or R9 with the amino acid or peptide.
  • Al a group other than an amino acid or a peptide
  • the method comprises coupling an amino acid or a peptide so as to replace Al with the amino acid or peptide.
  • Al is a OH, OP1, NH2, or N HP2 a nd/or R9 is hydrogen, an amino protecting group or L3-C(0), and the method comprises coupling a n amino acid or a peptide so as to replace Al and/or R9 with the amino acid or peptide.
  • Al is a OH, OP1, NH2, or N HP2 a nd R9 is hyd rogen, a n amino protecting group or L3-C(0) and the method further comprises coupling an amino acid or a peptide so as to replace Al and/or R9 with the amino acid or peptide.
  • coupling a peptide comprises individually coupling one or more amino acids and/or one or more peptides.
  • coupling the amino acid or peptide provides a peptide conjugate comprising a peptide epitope. In some embodiments, the coupling the amino acid or peptide provides a peptide conjugate comprising a linker group or one or more amino acids thereof. In some embodiments, coupling the amino acid or peptide provides a peptide conj ugate comprising a peptide epitope bound to the amino acid to which the lipid moieties a re conjugated via a linker group. In some embod iments, the Na-amino group of the amino acid comprising the thiol to which the lipid moieties are conj ugated is acylated . In some embodiments, R9 in the amino acid comprising conjugation pa rtner comprising the thiol is L3-C(0)-.
  • the method further comprises acylating the ⁇ -amino group of the amino acid of the amino acid conj ugate or the amino acid residue of the peptide conjugate to which the lipid moeities are conj ugated . In certain embodiments, the method further comprises acylating the ⁇ -amino group with a C2-20 fatty acid, such as acetyl.
  • R9 is hydrogen or an amino protecting group
  • the method further comprises acylating the amino acid conj ugate or peptide conjugate so as to replace the hydrogen or amino protecting group at R9 with L3-C(0).
  • acylating the amino acid conjugate or peptide conjugate so as to replace the amino protecting group at R9 with L3-C(0) comprises removing the amino protecting group at R9 to provide a hydrogen at R9.
  • the or an amino acid of the amino acid-comprising conjugation partner comprises the thiol.
  • an amino acid residue of the peptide of the peptide-containing conj ugation partner comprises the thiol .
  • the thiol is the thiol of a cysteine resid ue.
  • the cysteine residue is a terminal residue. In certain embodiments, the cysteine residue is an N-terminal residue.
  • the amino group of the cysteine residue is acylated .
  • the amino group is acylated with a C2-20 fatty acid.
  • the C2-20 fatty acid is acetyl or pa lmitoyl. In a nother exemplary embod iment, the C2-20 fatty acid is acetyl .
  • the amino acid-comprising conj ugation partner and/or peptide conjugate comprises from 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • the peptide-containing conj ugation partner comprises from 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises a peptide comprising from 8 to 60 amino acids. In one exemplary embod iment, the peptide comprises from 8 to 60 amino acids.
  • the amino acid-comprising conjugation pa rtner and/or peptide conjugate comprises from 5 to 220, 8 to 220, 5 to 175, 8 to 175, 8 to 150, 10 to 150, 15 to 125, 20 to 100, 20 to 80, 20 to 60, 25 to 100, 25 to 80, 25 to 60, 30 to 80, 40 to 60, or 50 to 60 amino acids.
  • the peptide-conta ining conj ugation partner comprises from 5 to 220, 8 to 220, 5 to 175, 8 to 175, 8 to 150, 10 to 150, 15 to 125, 20 to 100, 20 to 80, 20 to 60, 25 to 100, 25 to 80, 25 to 60, 30 to 80, 40 to 60, or 50 to 60 amino acids.
  • the amino acid comprising conjugation pa rtner and/or peptide conjugate comprises from 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • the peptide-containing conjugation partner comprises from 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • the amino acid comprising conjugation partner is a short peptide.
  • the short peptide comprises less than 10, 9, 8, 7, 6, 5, 4, or 3 amino acids.
  • the amino acid-comprising conjugation partner a nd/or peptide conjugate comprises one or more solubilising groups. In one embodiment, the peptide- containing conjugation partner comprises one or more solubilising groups.
  • the solubilising group is an amino acid seq uence comprising two or more hydrophilic amino acid residues in the peptide chain. In certain embodiments, the solubilising group is an amino acid sequence comprising a sequence of two or more consecutive hydrophilic amino acid residues in the peptide chain. In one embod iment, the hydrophilic amino acid resid ues a re cationic amino acid residues. In one
  • the cationic amino acid residues are arg inine or lysine residues. In one specifically contemplated embodiment, the cationic amino acid residues are lysine residues. In one embodiment, the sequence comprises from 2 to 20, 2 to 15, 2 to 10, 3 to 7, or 3 to 5 amino acids. In one embodiment, the solubilising group is a tri-, tetra-, penta-, hexa-, or hepta- lysine sequence. In one specifically contemplated embodiment, the solubilising group is a tetralysine sequence.
  • the peptide conj ugate and/or amino-acid comprising conjugation partner comprises a serine residue adjacent to the amino acid residue to which the lipid moeities are conjugated .
  • the peptide of the peptide-containing conjugation partner comprises a serine residue adjacent to the amino acid residue to which the lipid moeities are conjugated .
  • the amino acid residue to which the lipid moeities are conjugated is N -terminal.
  • the peptide further comprises a consecutive sequence of two or more hydrophilic amino acid residues adjacent to the serine residue.
  • the peptide conjugate and/or amino-acid comprising
  • conjugation partner comprises a consecutive sequence of two or more hydrophilic amino acid residues adjacent to the serine resid ue.
  • the peptide conjugate and/or amino acid-comprising are independently selected from the group consisting of: the peptide conjugate and/or amino acid-comprising
  • conjugation partner comprises only naturally occuring amino acids.
  • the peptide-containing conj ugation partner comprises only natura lly occuring amino acids.
  • 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, or 99% or more of the amino acid residues in the peptide are naturally occuring amino acids.
  • 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, or 99% or more of the amino acid residues in the peptide conjugate and/or amino acid-comprising conjugation pa rtner are naturally occuring amino acids.
  • the peptide conjugate and/or amino acid-comprising conjugation partner comprises a peptide comprising a peptide epitope.
  • the peptide of the peptide-containing conj ugation partner comprises one or more peptide epitopes.
  • the peptide comprises, consists essentia lly of, or consists of one or more EBV LM P2 epitopes.
  • the one or more EBV LMP2 epitopes a re MHCI epitopes.
  • the peptide comprises one or more EBV LMP2 epitopes selected from the group consisting of a ny one of SEQ ID NOs 76 - 101.
  • the peptide comprises a peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid seq uence of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises a peptide comprising or consisting of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprising or consisting of 20 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75. In various embodiments, the peptide comprises a recombina nt peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the recombinant peptide comprises or consists of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprises or consists of 20 or more contig uous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the peptide epitope is derived from NY-ESO-1.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous amino acid residues from any one of SEQ ID NO: 106, 107, 108, 113, 114, 119, 120, a nd 121.
  • the peptide comprises, consists essentia lly of, or consists of one or more NY-ESO-1 epitopes.
  • the one or more NY-ESO-1 epitopes a re MHCI epitopes.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous amino acid residues from a ny one of SEQ ID NO: 106, 107, 108, 113, 114, 119, 120, and 121.
  • the peptide comprises a peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NO: 106, 107, 108, 113, 114, 119, 120, and 121. In various embodiments, the peptide comprises a peptide comprising or consisting of 15 or more contiguous amino acids from the amino acid seq uence of a ny one of SEQ ID NO:
  • 106 107, 108, 113, 114, 119, 120, a nd 121, or comprising or consisting of 20 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NO: 106,
  • the reactive functional groups of the amino acids of the peptide-containing conjugation partner are unprotected.
  • one or more reactive functiona l groups of one or more amino acids of the peptide conjugate are unprotected.
  • one or more reactive functiona l groups of the amino acid of the amino acid conjugate are unprotected .
  • one or more reactive functiona l groups of one or more amino acids of the amino acid-comprising conjugation partner are unprotected .
  • the amino acid-comprising conjugation partner comprises a peptide, wherein the reactive functional groups of the side chains of the amino acids of the peptide are unprotected, with the exception of any thiols other than the thiol to be reacted .
  • the reactive functional groups of the amino acids of the peptide of the peptide-containing conjugation partner are
  • the reactive functional groups of the amino acids of the peptide of the peptide-containing conjugation partner are
  • the peptide of the peptide conjugate and/or peptide-containing conjugation partner may, as described herein, be optiona lly substituted, modified, or bound to va rious other moieties as described herein to provide the peptide conj ugate and/or peptide containing conjugation partner.
  • the method comprises
  • SPPS solid phase peptide synthesis
  • the method comprises
  • SPPS solid phase peptide synthesis
  • the method further comprises acylating the Na-amino group of the amino acid of the amino acid conj ugate or the amino acid to which the lipid-moieties are conjugated of any one of the peptide conj ugates.
  • the method comprises cleaving the peptide conj ugate from the solid phase support.
  • the method comprises
  • SPPS solid phase peptide synthesis
  • the method comprises
  • the peptide-containing conjugation partner is not purified prior to reaction with the lipid-containing conjugation partners.
  • one or more protecting groups are removed on cleaving the peptide from the solid phase support. In certain embodiments, a ll of the protecting groups present in the peptide are removed .
  • the SPPS is Fmoc-SPPS.
  • the amino acid residue in the peptide of the peptide-containing conjugation partner bea ring the thiol to be reacted is an N-terminal amino acid residue and the method comprises acylating the N-termina l amino group prior to cleaving the peptide from the solid phase.
  • the N-terminal residue is a cysteine resid ue.
  • the method further comprises separating the peptide conj ugate from the reaction med ium and optionally purifying the peptide conjugate.
  • the present invention broadly consists in a method of making a peptide conj ugate, the method comprising
  • the product peptide conjugate is a compound of the formula (I) or a pharmaceutically acceptable salt thereof of the present invention .
  • the amino acid of the amino acid conjugate is coupled under conditions that reduce epimerisation at the a-carbon of the amino acid .
  • the conditions are such that less than about 35, 30, 25, 20, 15, 10, 5, 3, 2, or 1% by mol of the amino acid is epimerised .
  • the conditions that reduce epimerisation comprise the use of PyBOP as the coupling reagent.
  • the conditions comprise the use of PyBOP and 2,4,6- trimethylpyridine.
  • the present invention broadly consists in use of an amino acid- or peptide-conjugate of the formula (I) of the present invention or a sa lt or solvate thereof in the synthesis of a n immunogenic peptide-conj ugate.
  • the immunogenic peptide conj ugate is a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention broadly consists in an amino acid-conjugate or peptide conj ugate of the present invention produced by a method of the present invention.
  • the present invention broadly consists in a peptide conjugate made by a method of the present invention.
  • the present invention broadly consists in a composition comprising an amino acid- or peptide conj ugate of formula (I) of the present invention or a salt or solvate thereof.
  • the composition comprises isolated, pure, purified or substantially purified compound of formula (I) or a sa lt or solvate thereof.
  • the composition comprises at least about 60, 70, 75, 80, 85, 90, 95, 97, 98, or 99% by weight compound of formula (I) or a sa lt or solvate thereof.
  • the composition is free of substantially free of amino acid- or peptide containing compounds other than compounds of formula (I).
  • the present invention broadly consists in a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a peptide conjugate compound of the formula (I) of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pha rmaceutically acceptable carrier.
  • the pharmaceutical composition of claim comprises an effective amount of two or more peptide conj ugate compounds of the formula (I) of the present invention.
  • the pharmaceutical composition is a n immunogenic composition.
  • the pharmaceutical composition does not include an extrinsic adjuvant.
  • the pharmaceutical composition is a vaccine.
  • the pharmaceutical composition comprises an effective amount of two or more peptide conj ugates of the present invention, for example the pharmaceutical composition comprises an effective amount of three or more peptide conjugates of the present invention.
  • the pharmaceutical composition comprises an effective amount of one or more peptide conjugates of the present invention together with one or more peptides described herein, or any combination thereof.
  • the pharmaceutical composition comprises an effective amount of two or more peptide conj ugates of the present invention a nd one or more peptides described herein, or an effective a mount of one or more peptide conjugates of the present invention and two or more peptides described herein.
  • the present invention broadly consists in a method of vaccinating or eliciting an immune response in a subject comprising administering to the subject an effective amount of one or more peptide conjugate compounds of the formula (I) of the invention or a pharmaceutically acceptable salt or solvate thereof, or a n effective amount of a pha rmaceutical composition of of the present invention.
  • the present invention broadly consists in use of one or more peptide conjugate compounds of formula (I) of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition of the present invention in the manufacture of a medicament for vaccinating or eliciting an immune response in a subject.
  • the present invention broadly consists in one or more peptide conjugate compounds of the formula (I) of the present invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition of the present invention for vaccinating or eliciting an immune response in a subject.
  • the present invention broadly consists in use of one or more peptide conjugate compounds of the formula (I) of the invention or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition of the present invention for vaccinating or eliciting an immune response in a subject.
  • the method, use, one or more compounds, or pharmaceutical composition is for eliciting an immune response in a subject.
  • the method, use, one or more compounds, or pharmaceutical composition is for vaccinating a subject.
  • the method comprises the administration of one or more peptides described herein and one or more peptide conjugates of the present invention or two or more peptide conjugates of the present invention, for example one or more peptides in combination with one or more peptide conjugates to the subject.
  • one or more peptides described herein and one or more peptide conjugates of the present invention or two or more peptide conjugates of the present invention, for example one or more peptides in combination with one or more peptide conjugates, are used for vaccinating or eliciting an immune response in the subject or in the manufacture of a medicament for vaccinating or eliciting an immune response in the subject.
  • two or more peptide conjugates are used or administered.
  • the two or more peptide conjugates, or one or more peptides and one or more peptide conjugates are used or administered simultaneously, sequentially, or separately.
  • Asymmetric centers may exist in the compounds described herein.
  • the asymmetric centers may be designated as (R) or (S), depending on the configuration of substituents in three dimensional space at the chiral carbon atom.
  • All stereochemical isomeric forms of the compounds, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof, including enantiomerically enriched and diastereomerically enriched mixtures of stereochemical isomers, are within the scope of the invention.
  • Individual enantiomers can be prepared synthetically from commercially available enantiopure starting materials or by preparing enantiomeric mixtures and resolving the mixture into individual enantiomers. Resolution methods include conversion of the enantiomeric mixture into a mixture of diastereomers and separation of the
  • the compounds described herein may also exist as conformational or geometric isomers, inlcuding c/ ' s, trans, syn, anti,
  • E
  • Z nd
  • isomers and a ny mixtures thereof are within the scope of the invention.
  • tautomeric isomers or mixtures thereof of the compounds described are any tautomeric isomers or mixtures thereof of the compounds described .
  • a wide variety of functiona l groups and other structures may exhibit tautomerism. Exa mples include, but are not limited to, keto/enol, imine/enamine, and thioketone/enethiol tautomerism.
  • the compounds described herein may also exist as isotopologues and isotopomers, wherein one or more atoms in the compounds are replaced with different isotopes.
  • Suitable isotopes include, for example, X H, 2 H (D), 3 H (T), 12 C, 13 C, 14 C, 1S 0, and 18 0. Proced ures for incorporating such isotopes into the compounds described herein will be apparent to those skilled in the art. Isotopologues a nd isotopomers of the compounds described herein a re also within the scope of the invention .
  • salts of the compounds described herein including pha rmaceutically acceptable salts.
  • Such salts include, acid addition salts, base addition salts, and quaterna ry salts of basic nitrogen-conta ining groups.
  • Acid addition salts can be prepa red by reacting compounds, in free base form, with inorganic or organic acids.
  • inorganic acids include, but are not limited to, hydrochloric, hydrobromic, nitric, sulfuric, a nd phosphoric acid .
  • Examples of orga nic acids include, but are not limited to, acetic, trifluoroacetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, stearic, salicylic, metha nesulfonic, benzenesulfonic, isethionic, sulfanilic, adipic, butyric, and piva lic.
  • Base addition salts can be prepa red by reacting compounds, in free acid form, with inorganic or organic bases.
  • inorganic base addition salts include alkali metal salts, alkaline earth metal sa lts, and other physiologically acceptable metal salts, for example, aluminium, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • organic base addition salts include amine salts, for example, salts of trimethylamine, diethylamine, ethanolamine, d iethanolamine, and ethylenediamine.
  • Quaterna ry salts of basic nitrogen-containing groups in the compounds may be may be prepared by, for example, reacting the compounds with a lkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl, a nd d iamyl sulfates, and the like.
  • a lkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, a nd d iamyl sulfates, and the like.
  • the compounds described herein may form or exist as solvates with various solvents. If the solvent is water, the solvate may be referred to as a hydrate, for example, a mono- hydrate, a d i- hydrate, or a tri-hydrate. All solvated forms and unsolvated forms of the compounds described herein are within the scope of the invention.
  • aliphatic is intended to include saturated and unsaturated, nonaromatic, straight cha in, branched, acyclic, and cyclic hydrocarbons.
  • aliphatic groups include, for exa mple, alkyl, a lkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)a lkyl and (cycloalkyl)a lkenyl groups.
  • aliphatic groups comprise from 1-12, 1-8, 1-6, or 1-4 carbon atoms.
  • aliphatic groups comprise 5-21, from 9-21, or from 11-21 carbon atoms, such as from 11, 13, 15, 17, or 19 carbon atoms.
  • the aliphatic group is saturated.
  • heteroaliphatic is intended to include aliphatic groups, wherein one or more chain and/or ring carbon atoms are independently replaced with a heteroatom, preferably a heteroatom selected from oxygen, nitrogen and sulfur. In some embodiments, the heteroaliphatic is saturated . Examples of heteroaliphatic groups include linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
  • alkyl is intended to include saturated straig ht chain a nd branched chain hydrocarbon groups.
  • alkyl groups have from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or from 1 to 4 carbon atoms.
  • a lkyl groups have from 5-21, from 9-21, or from 11-21 carbon atoms, such as from 11, 13, 15, 17, or 19 carbon atoms.
  • straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, a nd 2,2-dimethylpropyl.
  • alkenyl is intended to include stra ight and branched cha in a lkyl groups having at least one double bond between two carbon atoms.
  • a lkenyl groups have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms.
  • a lkenyl g roups have from 5-21, from 9-21, or from 11-21 carbon atoms, such as from 11, 13, 15, 17, or 19 carbon atoms.
  • alkenyl g roups have one, two, or three carbon-carbon double bonds.
  • alkynyl is intended to include stra ight and branched cha in a lkyl groups having at least one triple bond between two carbon atoms.
  • the alkynyl group have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms.
  • alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C ⁇ CH, -C ⁇ CH3, -CH2C ⁇ CH 3, and -C ⁇ CH 2 CH(CH2CH 3 )2.
  • heteroalkyl is intended to include alkyl groups, wherein one or more cha in carbon atoms are replaced with a heteroatom, preferably a heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroalkyl is saturated . Heteroalkyl groups include, for example, polyethylene glycol groups and polyethylene glycol ether groups, and the like.
  • cycloalkyl is intended to include mono-, bi- or tricyclic alkyl groups.
  • cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s).
  • cycloalkyl g roups have 5 or 6 ring ca rbon atoms.
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms.
  • Bi- and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1.1 ]hexanyl, bicyclo[2.2.1 ]heptanyl, adamantyl, and decalinyl.
  • cycloalkenyl is intended to include non-a romatic cycloalkyl groups having at least one double bond between two carbon atoms.
  • cycloa lkenyl groups have one, two or three double bonds.
  • cycloalkenyl groups have from 4 to 14, from 5 to 14, from 5 to 10, from 5 to 8, or from 5 to 6 carbon atoms in the ring(s).
  • cycloalkenyl groups have 5, 6, 7, or 8 ring carbon atoms.
  • cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexad ienyl, butadienyl, pentadienyl, and hexadienyl.
  • aryl is intended to include cyclic aromatic hydrocarbon groups that do not contain any ring heteroatoms.
  • Aryl groups include monocyclic, bicyclic and tricyclic ring systems. Examples of aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, penta lenyl, and naphthyl .
  • a ryl groups have from 6 to 14, from 6 to 12, or from 6 to 10 carbon atoms in the ring(s) .
  • the aryl g roups are phenyl or naphthyl .
  • Aryl g roups include aromatic-aliphatic fused ring systems. Examples include, but are not limited to, inda nyl and tetrahydronaphthyl .
  • heterocyclyl is intended to include non-aromatic ring systems containing 3 or more ring atoms, of which one or more is a heteroatom.
  • the heteroatom is nitrogen, oxygen, or sulfur.
  • the heterocyclyl group contains one, two, three, or four heteroatoms.
  • heterocyclyl groups include mono-, bi- a nd tricyclic rings having from 3 to 16, from 3 to 14, from 3 to 12, from 3 to 10, from 3 to 8, or from 3 to 6 ring atoms.
  • Heterocyclyl groups include partially unsaturated and saturated ring systems, for example, imidazolinyl and imidazolidinyl.
  • Heterocyclyl groups include fused and bridged ring systems conta ining a heteroatom, for example, quinuclidyl.
  • Heterocyclyl groups include, but are not limited to, azirid inyl, azetidinyl, azepanyl, diazepanyl, 1,3-dioxanyl, 1,3-d ioxolanyl, isoxazolid inyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrazolid inyl, pyrrolinyl, pyrrolidinyl, tetra hydrofuranyl, tetrahyd rothienyl, thiad iazolidinyl, and trithia nyl.
  • heteroaryl is intended to include aromatic ring systems containing 5 or more ring atoms, of which, one or more is a heteroatom.
  • the heteroatom is nitrogen, oxygen, or sulfur.
  • heteroaryl groups include mono-, bi- and tricyclic ring systems having from 5 to 16, from 5 to 14, from 5 to 12, from 5 to 10, from 5 to 8, or from 5 to 6 ring atoms.
  • Heteroa ryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl,
  • Heteroaryl groups include fused ring systems in which all of the rings are aromatic, for example, indolyl, and fused ring systems in which only one of the rings is aromatic, for example, 2,3-dihyd roindolyl.
  • halo or halogen is intended to include F, CI, Br, and I.
  • heteroatom is intended to include oxygen, nitrogen, sulfur, or phosphorus.
  • the heteroatom is selected from the g roup consisting of oxygen, nitrogen, and sulfur.
  • substituted is intended to mean that one or more hyd rogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituent/s are attached is not exceeded, and that the substitution results in a stable compound.
  • optional substituents in the compounds described herein include but are not limited to halo, CN, N0 2 , OH, N H 2 , N HR10, N R10R20, Cl- 6haloalkyl, Cl-6ha loalkoxy, C(0)NH 2 , C(O)NHR10, C(O)N R10R20, SO2RIO, OR10, SR10, S(O)R10, C(O)R10, and Cl-6aliphatic; wherein RIO a nd R20 are each independently Cl- 6aliphatic, for example Cl-6alkyl .
  • carboxyl protecting group is mea ns a group that is capable of readily removed to provide the OH group of a carboxyl group and protects the carboxyl group aga inst undesirable reaction during synthetic procedures.
  • Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et a l. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455- 2504.
  • Examples include, but are not limited to, a lkyl a nd silyl g roups, for example methyl, ethyl, terf-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and terf-butyldimethylsilyl, and the like.
  • amine protecting group means a group that is capable of being readily removed to provide the NH2 group of a n amine group and protects the amine group against undesirable reaction during synthetic proceed ures.
  • Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et a l. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455- 2504.
  • Examples include, but are not limited to, acyl and acyloxy groups, for example acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyi, aminocaproyl, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxyca rbonyl, 2- trimethylsilylethoxy-carbonyl, terf-butyloxycarbonyl, benzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2,4-d ichloro-benzyloxycarbonyl, and the like.
  • acyl and acyloxy groups for example acetyl, chloroacetyl, trichloroacet
  • Cbz carboxybenzyl
  • Nosyl (0- or p-nitrophenylsulfonyl
  • Bpoc (2-(4- biphenyl)isopropoxycarbonyl)
  • a nd Dde l-(4,4-dimethyl-2,6-dioxohexylidene)ethyl
  • carboxamide protecting group means a group that is capable of being readily removed to provide the NH2 group of a carboxamide g roup and protects the carboxamide g roup against undesirable reaction during synthetic procedures.
  • Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al . (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504.
  • Examples include, but are not limited to, 9-xa nthenyl (Xan), trityl (Trt), methyltrityl (Mtt), cyclopropyldimethylcarbinyl (Cpd), and dimethylcyclopropylmethyl (Dmcp) .
  • Xan 9-xa nthenyl
  • Trt trityl
  • Mtt methyltrityl
  • Cpd cyclopropyldimethylcarbinyl
  • Dmcp dimethylcyclopropylmethyl
  • the invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individua lly or collectively, in a ny or all combinations of two or more of sa id parts, elements or features, and where specific integers a re mentioned herein which have known equiva lents in the art to which the invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.
  • Figure 1 is an HPLC chromatogram of reaction mixture following irradiation of solution of AcCSKKKKNLVPC(tBu)VATV 1, vinyl palmitate (70 equivalents) and DM PA at 365 nm.
  • Peak a (11.05 min) residual starting peptide 1
  • b (18.58 min) mono-pamitoylated petide 2
  • c (26.66 min) bis-pa lmitoylated peptide 3
  • e, f sulfoxides of 2 and 3
  • * byprod ucts from the DM PA photoinitiator.
  • Figure 2 is a low-resolution mass spectrum of peak b from Figure 1 : m/z (ESI) 999.9 [M + 2H + ].
  • Figure 3 is a low-resolution mass spectrum of peak c from Figure 1 : m/z (ESI) 1141.3 [M + 2H + ].
  • Figures 4A-4C are g raphs showing the results of the TLR agonism assay using the peptide conjugates and HekBlueTM, as described herein in the Examples.
  • A SEAP production in HEK-BlueTM-mTLR2 cells (left) and HEK-BlueTM-hTLR2 cells (right) elicited by agonists 520, 550, 530, 540, 510 or PBS.
  • B SEAP production in HEK-BlueTM-mTLR2 cells (left) a nd H EK-BlueTM-hTLR2 cells (right) elicited by agonists 520 (grey bars) a nd 530 (black ba rs).
  • C SEAP production in HEK-BlueTM-mTLR2 cells (left) and HEK-BlueTM- hTLR2 cells (right) elicited by agonists 550 (grey bars) and 530 (black bars).
  • Figures 4D and 4E are graphs showing T cell clone activation in response to D: agonists 521 (black ba rs), 551 (cross-hatched bars) and 511 (g rey bars) ; E: agonists 552 (cross- hatched bars), 512 (black bars) a nd 500 (g rey bars).
  • Figure 5 is a n l NM R spectrum of bis-pamitolyated peptide 3.
  • Figures 6A and 6B a re graphs showing the results of TLR agonism assays in HEK-BlueTM- mTLR2 ( Figure 6A) and HEK-BlueTM-hTLR2 ( Figure 6B) cells using PamlCys-SKKKK- NH 2 and the (R)- a nd (S)- Pam2Cys-SKKKK, Pa m3Cys-SKKKK, a nd homoPam2Cys- SKKKK constructs listed in Table 4, as described in Example 8, at various concentrations : 10 "s mol/L (black bars), 10 "7 mol/L (da ry grey bars), 10 "8 mol/L (medium grey ba rs), 10 "9 mol/L (d iagonal cross-hatched bars), 10 "10 mol/L (light g rey bars), and 10 "11 mol/L (squa re hatched ba rs).
  • the present invention provides amino acid- and peptide conj ugate compounds of the formula (I) as defined herein.
  • the inventors have advantageously found that such conjugates have surprising immunogenic activity.
  • amino acid- and peptide conj ugate compounds of formula (I) may be prepared using the methods and proceed ures described herein.
  • Starting materia ls and/or intermediates useful in the methods may be prepared using known synthetic chemistry techniques (for example, the methods generally described in Louis F Fieser and Ma ry F, Reagents for Organic Synthesis v. 1-19, Wiley, New York (1967-1999 ed .) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed . Springer- Verlag Berlin, including supplements (also ava ilable via the Beilstein online database)) or, in some embodiments, may be commercially available.
  • Preparation of the compounds may involve the protection a nd deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by a person skilled in the art.
  • Protecting groups and methods for protection and deprotection a re well known in the art (see e.g. T. W. Greene and P. G. M . Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999)) .
  • compounds of formula (IF) that are compounds of formula (I) wherein w is 1, v is 0, and m is from 2 to 6, preferably 2, may be prepa red via a method involving the conjugation of an epoxide to an amino acid- comprising conjugation partner.
  • the present invention provides a method of ma king a compound of the formula (XV), comprising reacting a n epoxide of the formula (XVI) and an a mino acid-comprising conjugation partner comprising a thiol of the formula (III) under cond itions effective to provide the compound of formula (XV) by conj ugation of the thiol to the epoxide.
  • the amino acid comprising conjugation partner reacted with the epoxide may consist of an amino acid, for example an ⁇ -amine protected and/or C-terminus protected cysteine.
  • the amino acid comprising conj ugation partner may comprise a peptide, for example a short peptide.
  • the amino acid comprising conj ugation partner may comprise about 15 amino acid residues or less, for example 5, 4, or 3 amino acid residues.
  • the Na-amino group of the amino acid comprising conj ugation pa rtner is preferably protected or otherwise substituted (i.e. is not in the form of a free amine -NH2 group) to prevent reaction during the conjugation reaction.
  • the C-terminus of the amino acid comprising conjugation partner may also be protected .
  • X10 in the compound of formula (XVI) may be a protected hyd roxyl, thiol, amine, or carbamate group (P10-O-, P11-S-, P12-N R-, or P12-N RC(0)0-, respectively) from which Ll-Zl- a nd L2-Z2- may subsequently be formed.
  • the protecting group may be removed in the conjugation reaction to provide a compound of the formula (XV) wherein XI 1 is the corresponding deprotected group.
  • XI 1 is the corresponding deprotected group.
  • X10 is a PIO-O- group conjugation may provide the corresponding hydroxyl group as Xl l in the compound of formula (XV).
  • the epoxide of formula (XVI) comprises a stereogenic centre at the carbon atom to which R3 is attached .
  • a sing le stereoisomer of the epoxide or a stereoisomerically enriched mixture of the epoxide may used in the reaction to control the stereochemistry of the carbon atom to which R3 is attached in the compound of formula (XV) a nd subsequent products formed, including the compound of formula (IF).
  • Va rious methods for providing ena ntiopure or ena ntioenriched mixtures of epoxides are known in the a rt.
  • providing the single stereoisomer or a stereoisomerically enriched mixture of the epoxide of formula (XVI) comprises resolving a racemic mixture of the epoxide.
  • resolving a racemic epoxide mixture by kinetic hydrolysis as described by Jacobsen et al, Science, 1997, 277, 936-938.
  • the epoxide of formula (XVI) may be provided by reacting an alkene of the formula (XVII) with an oxidant under conditions effective to epoxidise the alkene.
  • an oxidant under conditions effective to epoxidise the alkene.
  • Numerous methods for epoxidising alkenes are known in the art. In certa in embodiments, the epoxidation is carried out by reacting the alkene with a peroxide or an orga nic N-oxide as the oxida nt.
  • suitable peroxides include organic peroxides, for example m- chloro peroxybenzoic acid .
  • N-oxides include, for example, pyridine N-oxide and the like. Other suitable oxidants will be apparent to those skilled in the art.
  • the reaction may be carried out in a liquid reaction medium comprising a suitable solvent, for example dichlorometha ne.
  • a suitable solvent for example dichlorometha ne.
  • Alkenes of the formula (XVII) may be commercially ava ilable or prepared from commercially ava ilable precursors using standa rd synthetic chemistry techniques.
  • certa in X10 groups may be susceptible to oxidation in the epoxidation reaction, for example when X10 comprises an amine group (which may form an N-oxide) or thioether group (which may form e.g . sulfoxides or sulfones). Such groups may be protected d uring the reaction to prevent oxidation or reduced back to the desired group at an appropriate point in the synthetic sequence after the epoxidation reaction has been carried out.
  • the epoxide of formula (XVI) may be prepared by treating a compound of formula (XVII-A), wherein LG is a suitable leaving group such as a halogen, with a base in a suitable solvent to displace the leaving group as shown in scheme A2.
  • Compounds of the formula (XVII-A) may be commercially available or may be prepared from commercially ava ilable precursors. Adva ntageously, in some embodiments, the compound of formula (XVII-A) may be prepared from a n enantiopure a-amino acid . The epoxidation reaction proceeds stereospecifica I ly with inversion of stereochemistry at the carbon to which R3 is attached .
  • the compound of formula (XVII-A1) which corresponds to a compound of formula (XVII-A) wherein m is 2 and each Rl and R2, a nd R3, R4, a nd R5 are hydrogen, X10 is -OH, and LG is bromo, may be prepared from L- aspartic acid (see Volkmann, R. A. et al . J. Org. Chem., 1992, 57, 4352-4361).
  • L-Aspartic acid may be converted to be bromosuccinic acid (AA-1) by, for example, treatment with sodium nitrite and a strong acid such as sulfuric acid, to generate nitrous acid in situ, in the presence of sodium bromide at a temperature from -10 to 0°C.
  • the reaction proceeds stereospecifically with overall retention of stereochemistry.
  • Reduction of bromosuccinic acid (AA-1) to bromodiol (XVII-A1) may be carried out using a suitable reductant, for example by treatment with bora ne or borane-dimethyl sulfide complex in TH F at -78°C allowing the reaction mixture to warm to room temperature.
  • Epoxidation to provide the compound of formula (XVI-la) may be carried out by reacting bromodiol (XVII-A1) with a base, for example cesium carbonate in dichloromethane at room temperature. As noted above, the reaction proceeds stereospecifcally with overall inversion of stereochemistry.
  • the compound of formula (XV) may be subsequently converted by one or more synthetic steps to an amino acid or peptide conjugate of the formula (IF).
  • the hydroxyl group bound to the carbon to which R3 is attached is converted to an L2-Z2- group.
  • the one or more steps also comprises converting Xll to Ll-Zl- .
  • the Ll-Zl- and L2-Z2- groups may be introduced simultaneously or sequentially in any order.
  • the one or more steps comprises acylating the compound of formula (XV) so as to replace the hydrogen atom of the hydroxyl group bound to the carbon to which R3 is attached with L2-C(0)-.
  • X10 is PIO-O- or OH; and Xll is PIO-O- or OH.
  • Xl l is PIO-O- or OH; and the one or more synthetic steps comprise acylating the compound of formula (XV) so as to replace P10 or the hydrogen atom of the hydroxyl group of Xl l with Ll-C(O)-; and/or the hydrogen atom of the hydroxyl group bound to the carbon to which R3 is attached with L2-C(0)-.
  • the method comprises reacting an epoxide of formula (XVI-1) bearing a protected hydroxyl group with an amino acid comprising conjugation partner of the formula (III) to provide a compound of the formula (XV-la).
  • Scheme A3 Preparation of bis-ester conj ugates via epoxide conj ugation.
  • the conjugation reaction may be carried out under acid ic cond itions by reacting the epoxide and thiol in the presence of an acid, for example hydrochloric acid, sulfuric acid, or a mixture thereof.
  • the reaction may be carried out in a liquid reaction medium comprising a suitable solvent, such as dichloromethane, at a temperature from about -10 to about 50°C, for example from 0 to 40°C.
  • the hydroxyl protecting group P10 is selected such that it is removable under the conditions effective for conjugation and is therefore removed during the conjugation reaction to provide the desired d iol of formula (XV-la).
  • Suitable protecting groups will be apparent to those skilled in the a rt a nd may include, for example, acid labile silyl protecting groups.
  • the conj ugation reaction may be carried using an epoxide of the formula (XVI) wherein X10 is a hydroxyl group, such as the epoxide of formula (XVI-la).
  • the diol of the formula (XV-la) may be converted to the compound of formula (IF-1) by reaction with the compounds of formula (VI-1) and (VI), wherein X is OH or a suitable leaving group (for example a halide, such as chloro or bromo), under conditions effective for esterification.
  • X is OH or a suitable leaving group (for example a halide, such as chloro or bromo), under conditions effective for esterification.
  • the cond itions effective for esterification depend on the nature of the compound of formula (IV) and/or (VI-1).
  • the reaction may be carried out in the presence of a base, such as DMAP, and activating agent, such as ⁇ , ⁇ '- diisopropylcarbod iimide (DIC) in a liquid medium comprising a suitable solvent, such as THF.
  • a base such as DMAP
  • activating agent such as ⁇ , ⁇ '- diisopropylcarbod iimide (DIC)
  • DIC ⁇ , ⁇ '- diisopropylcarbod iimide
  • THF a suitable solvent
  • the compound of formula (VI) and (VI-1) are identical.
  • the compound of formula (VI) and (VI-1) may each be palmitic acid.
  • conversion of the diol of formula (XV-la) to the compound of formula (IF- 1) may be accomplished in a single step.
  • different LI and L2 groups may be introduced by reacting the diol with a stoichiometric amount of a compound of formula (VI-1) or (VI) to esterify the more reactive of the two alcohols, and then reacting the resultant ester with the other a compound of formula (VI) or (VI-1) to esterify the second alcohol of the diol.
  • the method comprises reacting an epoxide of formula (XVI-1) and an amino acid comprising conjugation partner of the formula (III) to provide a compound of the formula (XV-lb) as shown in Scheme A4 below.
  • the hydroxyl protecting group P10 is stable and is not removed under the conjugation reaction conditions.
  • the protected alcohol of the formual (XV-lb) provides ready access to compounds of formula (IF-1) wherein LI and L2 are different.
  • Using the compound of formula (XV-lb) to access such compounds, rather than the diol of formula (XV-la), may be more convenient in certain emboidments, for example where there is poor selectivity between the alcohols of the diol of formula (XV-la).
  • the ⁇ -sulfanylhydroxyl group of the compound of formula (XV-lb) may be acylated with a compound of formula (VI) under conditions effective for esterification to provide protected ester (XVIII), then the protecting group P10 removed to provide the alcohol of formula (XIX).
  • the conditions for removal of the protecting group depend on the protecting group used . For example, dilute HF may be used to remove silyl protecting groups, such as TBDMS, TBDPS, a nd the like.
  • the alcohol of formula (XIX) may then be acylated with a compound of formula (VI-1) under conditions effective for esterification to provide the desired compound of formula (IF-1).
  • hyd roxyl groups for example those in the compounds of formulae (XV-la), (XV-lb), and (XIX), may be converted to various other functiona l groups, such as thiols and amines, to provide access compounds of formula (I) bearing Ll-Zl- and L2-Z2- g roups other tha n esters.
  • the compound of formula (XV-l b) can be used to prepare thioester and amide analogues of the compound of formula (IF-1), as shown below in Scheme A5.
  • amide ana logue (IF-3) the hydroxyl group in the compound of formula (XV-lb) may first be converted to an azide and then reduced to the corresponding amine.
  • the reaction may be carried out under modified M itsunobu cond itions (e.g. L. Rokhum et al, J. Chem. Sci, 2012, 124, 687-691) using PP i3, I2, imidazole, and Nal ⁇ b to provide the azide, and then PPh3 to reduce azide to the amine.
  • the azide may be obtained by first converting the hyd roxyl group to a suitable leaving g roup, for example a tosyl or mesyl group, and then treating with Nal ⁇ b.
  • acylation reaction may be carried out by reacting a carboxylic acid of the formula (VI) in the presence of a base, for example DMAP, and an activating agent, for example DIC, in a suitable solvent such as THF.
  • a base for example DMAP
  • an activating agent for example DIC
  • a suitable solvent such as THF
  • Thioester analogue may be prepared by first reacting the compound of formula (XV-lb) under Mitsunobu conditions (e.g. PPh3, diethylazodicarboxylate (DEAD)) and trapping with the desired thioacid of formula (VI-2), for example thiopalmitic acid, to provide the compound of formula (XVIII-l)(see e.g. 0. Schulze et al, Carbohydrate Res., 2004, 339, 1787-1802). Deprotection of the protecting group P10 and esterification of the resultant alcohol (XIX-1) provides the compound of the formula (IF-2).
  • Mitsunobu conditions e.g. PPh3, diethylazodicarboxylate (DEAD)
  • VEAD diethylazodicarboxylate
  • VI-2 diethylazodicarboxylate
  • thiopalmitic acid for example thiopalmitic acid
  • Thioester and amide analgoues of bis-ester may also be prepared from the compound of formula (XIX), as shown in Scheme A6.
  • the compound of formula (XIX) may be converted to the compound of formula (IF-4) by methods analogous to those described above for the conversion of the compound formula (XV-lb) to the compound of formula (XVIII-1).
  • the compound of formula (XIX) may be converted to the compound of formula (IF-5) by methods analogous to those described above for the conversion of the compound of formula (XV-lb) to the compound of formula (XVIII-2).
  • Scheme A6 Preparation of thioesters and amides via the compound of formula (XIX).
  • analogues of bis-ester (IF-1) may be prepared by replacing the compound of formula (XIX) in Scheme A6 with a compound of formula (XIX-1) or (XIX-2) and then following the synthetic sequences described .
  • Compounds of formula (I) may also be prepared by a method comprising the conj ugation of a n amino acid comprising conjugation partner and an aceta l, as shown in Scheme Bl .
  • the present invention provides a method of ma king the compound of formula (XX) comprising reacing an amino acid comprising conjugation pa rtner of the formula (III) and an acetal of the formula (XXI), wherein LG is a suitable leaving group, under conditions effective to provide a compound of the formula (I).
  • the thiol of the compound of formula (III) displaces the leaving group (LG) in the aceta l of formula (XXI).
  • Suitable leaving groups include but are not limited to halo (for example chloro, bromo, or iodo) or sulfonate (for example a tosylate or mesylate). Other suitable leaving groups will be apparent to those skilled in the a rt.
  • the size of the aceta l ring in the compound of formula (XXI) may vary.
  • the acetal ring may comprise from 5 to 7 ring atoms (i .e. may be a 5-7-membered cyclic acetal).
  • the cyclic acetal is 6-membered . It will be appreciated that when the cyclic acetal is a 5-membered cyclic acetal, in order to provide a compound of the formula (I), w is at least 2 (such that the sum of m, v, and w is at least 3).
  • the amino acid comprising conjugation partner reacted with the aceta l may consist of an amino acid, for example an ⁇ -amine protected and/or C-terminus protected cysteine.
  • the amino acid comprising conj ugation partner may comprise a peptide, for example a short peptide.
  • the amino acid comprising conj ugation partner may comprise about 15 amino acid residues or less, for example 5, 4, or 3 amino acid residues.
  • the Na-amino group of the amino acid comprising conj ugation pa rtner is preferably protected or otherwise substituted (i.e. is not in the form of a free amine -NH2 group) to prevent reaction during the conjugation reaction .
  • the C-terminus of the amino acid comprising conjugation partner may a lso be protected .
  • the conjugation reaction may be carried out in the presence of a base.
  • the reaction may be carried out in the presence of organic amine, in a suitable solvent, for example DMF, at a temperature of about 50°C.
  • suitable organic amines include but a re not limited to triethylamine, N-methylmorpholine, collidine, and the like.
  • the compound of formula (XXI) may be provided in stereoisomerically pure form or a stereoisomerically enriched mixture by reacting stereoisomerically pure or a
  • stereoisomerically pure compounds of formula (XXII) are readily commercially available, such as (4R)- or (4S)-(2,2-dimethyl-l,3-dioxa n-4-yl)-methanol.
  • a compound of formula (XXII-B), wherein Pg is a suitable hydroxyl protecting group may be reacted with a compound of the formula (XXII-C1) to provide the acetal of formula (XXII-D), which may then be converted to the compound of formula (XXII) by removal of the protecting group Pg .
  • the compound of formula (XXII-B) may be reacted with an acyclic acetal of the formula (XXII-C2), wherein Ro a nd Rp a re each independently Cl-4a lkyl.
  • the acetylisation reaction may be carried out using an acid, such as camphorsulfonic acid, in a suitable solvent, such as dichloromethane.
  • a silyl ether protecting group such as TBDMS
  • TBDMS tetrabutylammonium fluoride
  • suitable solvent such as THF
  • compounds of formula (XXI) may be prepared from compounds of formula (XXII) by reaction with a suitable precursor of the leaving group.
  • a suitable precursor of the leaving group For example, tosylate or mesylate leaving groups may be prepa red by reaction with tosyl chloride or mesyl chloride in the presence of a base and a suitable solvent, and an iodo leaving group may be prepared by reaction with PPh3 and I2.
  • the compound of formula (XX) may subsequently be converted by one or more synthetic steps to a compound of the formula (I), for example a compound of the formula (IA).
  • the one or more synthetic steps may comprise removing the acetal to provide a diol of the formula (XXIII-1).
  • the hydroxyl group bound to the carbon to which Rl and R2 are attached in the compound of formula (XXIII-1) may be converted to L1-Z1-, and/or the hydroxyl group bound to the carbon to which Rx and Ry are attached may be converted to L2-Z2.
  • the acetal in the compound of formula (XX) may be removed to provide the diol of formula (XXIII-1) by treatment with an acid such as p- toluene sulfonic acid in a solvent such as dichloromethane.
  • the diol of formula (XXIII-1) may be converted to the bis-ester compound of formula (IA) via one or more acylation steps in a manner analogous to that described for the conversion of the compound of formula (XV-la) to the compound of formula (IF-1).
  • the one or more synthetic steps may comprise removing the acetal to provide a compound of the formula (XXIII-2) or (XXIII- 3).
  • the one or more steps may comprise converting the hydroxyl group bound to the carbon atom to which Rx and Ry are attached in the compound of formula (XXIII-2) to L2-Z2-, removing the RmRnCH- group to provide a hydroxyl group, and converting the hydroxyl group to Ll-Zl ; or converting the hydroxyl group bound to the cabon to which Rx and Ry are attached in the compound of formula (XXIII-2) to L1-Z1-, removing the RmRnCH- group to provide a hydroxyl group, and converting the hydroxyl group to L2- Z2-.
  • Such methods advantageously allows allow the introduction of d ifferent Ll-Zl and L2-Z2- groups.
  • the acetal in the compound of formula (XX) may be removed by, for example, treatment with a suitable reducing agent, for example
  • the resulting compound of formula compound of formula (XXIII-2) may then be acylated with the compound of formula (VI) to introd uce the desired L2-C(0)0- group. Removal of the RmRnCH- group to provide the compound of formula (XXV-2) may be carried out by hydrogenolysis (e.g . for a benzyl or p- methoxybenzyl group) or any other suitable method having regard to the nature of RmRnCH- group.
  • the compound of formula (XXV-2) may then be converted to the compound of formula (IA) by acylating with the compound of formula (IV-1).
  • the acylation steps may be carried out as described herein with respect to the preparation of the compound of formula (IF-1).
  • compounds of formula (IA) may be prepared from compounds of formula (XXIII-3) by a replacing the compounds of formulae (XXIII-2), (VI) and (VI-1) in Scheme B3 with the compounds of formulae (XXIII-3), (VI-1), and (VI), respectively, and then following the synthetic sequence described .
  • Hydroxyl groups produced on removal of the acetal or RmRnCH- group such as those in the compounds formulae (XXIII-1), (XXIII-2), (XXIII-3), and (XXV-2), may be converted to various other functional groups, such as thiols and amines, to provide access compounds of formula (I) bearing other Zl a nd Z2 groups.
  • amide and thioester analogues of the bis-ester compound of formula (IA) may be prepared by methods analogous to those described above with respect to the amide a nd thioester analog ues of the bis-ester compound of formula (IF- 1).
  • the present invention also provides a method for preparing compounds of formula (I) via a thiol-ene reaction.
  • the method comprises reacting a first lipid-containing conjugation partner comprising a carbon-carbon double bond, a second lipid-containing conj ugation partner a carbon-carbon double bond, and an amino acid-comprising conjugation pa rtner comprising a thiol, under conditions effective to conjugate the first and second lipid- containing conjugation partners to the amino acid-comprising conj ugation partner.
  • Each lipid containing conjugation pa rtner comprises and therefore in the reaction provides to the compound of formula (I) a lipid moiety one comprising LI, the other comprising L2.
  • the thiol-ene reaction involves the addition of a thiol across a non-aromatic carbon- carbon double bond (i.e. hydrothiolation of the carbon-carbon double bond).
  • the reaction proceeds via a free radical mechanism.
  • There are three distinct phases in the reaction initiation, coupling, a nd termination.
  • radical generation gives rise to an electrophilic thiyl radical which propagates across the ene group of an a lkene, forming a carbon-centred radical and chain tra nsfer from an additional thiol molecule quenches the radica l on carbon to give the fina l prod uct.
  • the thiol is conjugated to a carbon atom of the carbon-carbon double bond of the first lipid conta ining conjugation pa rtner to form a carbon-centred radical, and that this carbon-centred radical, instead of being quenched, is then conjugated with a carbon atom of the carbon-carbon double bond of the second lipid-containing conjugation partner to provide a compound of the formula (I).
  • the method thus provides amino acid- and peptide conj ugates of the formula (I) in which the sulfur atom from the thiol is conj ugated to a carbon atom from the carbon-carbon double bond of the first lipid-conta ining conjugation pa rtner, and a carbon atom from the carbon-carbon double bond of the first lipid-containing conjugation partner is conjugated to a carbon atom from the carbon-carbon double bond of the second lipid-conta ining conjugation partner.
  • the first and second lipid containing conjugation partners may be the same or different. Those skilled in the art will appreciate that reacting different lipid containing conj ugation partners at the same time may provide a mixture of (potentially up to four different) compounds of formula (I). According ly, in certain exemplary embodiments, the first and second lipid containing conjugation partners are the same.
  • the thiolene reaction may be reg ioselective with respect to which carbon atom of the carbon-carbon double bond of the first lipid-containing conj ugation partner is conj ugated to the thiol a nd also with respect to which carbon atom of the carbon-carbon double bond of the second lipid-containing conj ugation pa rtner is conjugated to which carbon atom of the carbon-carbon double bond from the first lipid-conta ining conjugation partner.
  • Those skilled in the art will appreciate that various regioisomers may be formed in the reaction.
  • the method comprises reacting a first lipid containing conjugation partner of the formula (IIA) and a second lipid conta ining conj ugation partner of the formula (IIB) with a thiol containing amino acid comprising conj ugation partner (III) under conditions effective to provide a compound of the formula (IB) (Scheme CI).
  • the cond itions effective for formation of the compound of formula (IB) may vary.
  • the conditions effective for formation of the compound of formula (IB) may comprise carrying out the reaction with a stoichiometric excess of lipid containing conjugation partner to thiol, such as a stoichiometric ratio of the lipid containing conjugation partners (IIA) and (IIB) (combined) to amino acid-comprising conjugation partner of at least 7: 1, for exa mple 8 : 1, 9: 1, 10 : 1, 20 : 1, 30: 1, 40: 1, 50 : 1, 60: 1, or 70 : 1.
  • the degree of conversion of the amino acid-comprising conjugation partner to the prod uct compound of formula (IB) may vary. Preferably, at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, or 70% of the amino acid-comprising conjugation partner is converted to the compound of formula (IB) . Conversion may be determined by HPLC.
  • reaction of the a lkene of formula (IA) with the thiol of formula (III) results in the formation of a carbon-centred radical of the formula (X), which is trapped with the second alkene of the formula (IIB), rather than quenched by abstraction of a proton from the thiol of another molecule of the formula (III), to provide the desired amino acid- or peptide conj ugate.
  • the reaction may result in the production of a mixture of stereoisomers as it may not be possible to control or influence the stereochemistry of bond formation between the carbon atom to which R3 is bound and the carbon atom to which Rb and Rc are bound owing to the radical intermediate generated in the course of the reaction.
  • the reaction typically produces a mixture of epimers with respect to the carbon atom to which R3 is bound.
  • the Zl and Z2 in the lipid conta ining-conj ugation partners are each -C(0)0-, a nd the compound of formula (I) formed in the thiolene method is a compound of formula (IC) as defined herein.
  • the thiolene method of the present invention comprises reacting a n amino acid-comprising conj ugation partner comprising a structure of the formula (III) with lipid containing-conj ugation partners of the formula (IIA) a nd (IIB) that are vinyl esters to provide a compound of the formula (ID).
  • the reaction may be carried out, for example as described in the Exa mples below, by irradiating a reaction mixture comprising the amino acid comprising conj ugation pa rtner; lipid containing- conjugation partners; a photochemical initiator, such as DMPA.
  • One or more additives may be included that reduce the formation of by products, such as a sterically hindered thiol (for example tert-butylmercaptan), an acid (for example TFA), or a n organosilane (for example triisopropylsila ne), or a combination of any two or more thereof.
  • the reaction may be carried out in a suitable solvent, such as N MP, at ambient temperature for a suitable period of time, such as 30 minutes.
  • the reaction is typically initiated by the generation of one or more free radicals in the reaction mixture.
  • One or more free radicals may be generated in the method by any method known in the art.
  • the free radicals may be generated thermally and/or photochemically.
  • One or more free radical initiators may be used to initiate the generation of free radicals. Suitable free radical initiators include thermal initiators and photoinitiators.
  • Free radicals are generated from thermal initiators by heating .
  • the rate of degradation of the thermal initiator and resulting free radical formation depends on the initiator a nd the temperature at which the initiator is heated . Higher temperatures genera lly result in faster decomposition. A person skilled in the art will be able to select an appropriate temperature for heating the initiator without undue experimentation.
  • thermal initiators are commercia lly available.
  • thermal initiators include but a re not limited to terf-amyl peroxybenzoate, 1, 1'- azobis(cyclohexanecarbonitrile), 2,2'-azobisisobutyronitrile (AIBN ), benzoyl peroxide, tert-butyl hydroperoxide, tert-butyl peracetate, tert-butyl peroxide, tert-butyl peroxybenzoate, tert-butylperoxy isopropyl carbonate, la uroyl peroxide, peracetic acid, and potassium persulfate.
  • Free radicals may be generated from photoinitiators by irradiation with light.
  • the frequency of light necessary to induce degradation of the photoinitiators and free radical formation depends on the initiator.
  • Many photoinitiators can be initiated with ultraviolet light.
  • Light of a specific wavelength or wavelength ra nge may be used to selectively irradiate the initiator, where the lipid-conta ining conjugation partners or amino acid-comprising conjugation partner, for example a peptide-containing conj ugation partner, comprises photosensitive groups.
  • a frequency of about 365 nm is used . Light of this frequency is generally compatible with the side chains of natura lly occurring amino acids.
  • photoinitiators include but a re not limited to acetophenone, anisoin, anthraquinone, anthraquinone-2- sulfonic acid, benzil, benzoin, benzoin ethyl ether, benzoin isobutyl ether, benzoin methyl ether, benzophenone, 3,3',4,4'-benzophenonetetracarboxylic d ianhydride, 4- benzoylbi phenyl, 2-benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone, 4'- bis(diethylamino)benzophenone, 4,4'-bis(dimethylamino)benzophenone,
  • the initiator is present in the reaction in a stoichiometric ratio relative to the starting material comprising the thiol of from about 20: 1 to about 0.05: 1, from about 10 : 1 to about 0.05 : 1, from about 5 : 1 to about 0.05: 1, from about 3: 1 to about 0.5: 1.
  • the lipid-conta ining conjugation partners a nd amino acid-comprising conjugation partner may be prepared using known synthetic chemistry techniq ues (for example, the methods generally described in Louis F Fieser and Mary F, Reagents for Organic Synthesis v. 1-19, Wiley, New York (1967-1999 ed. ) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag Berlin, including supplements (also ava ilable via the Beilstein online database)) or, in some embodiments, may be commercially available.
  • lipid-containing conjugation partner compounds of the formula (IIA-1) may be prepared by reacting a compound of the formula (VI) wherein X is OH or a suitable leaving group with a compound of the formula (VII) wherein Y is H, a metal or meta lloid, or acyl (for example, alkylcarbonyl) under conditions effective for esterification (or transesterification where Y is an acyl g roup) (Scheme C2).
  • esterification or transesterification
  • X is chloro and Y is H
  • the reaction may be carried out in the presence of a base, such as pyridine or triethylamine, in a suitable solvent.
  • the acid chloride may be converted in situ to a more reactive species (e.g. to the correspond ing iodide, using sodium iod ide).
  • the temperature at which the reaction is carried out depends on the reactivity of the acid species and the solvent used .
  • vinyl esters of the formula (IIA-1) may be produced by transesterification with vinyl acetate (itself produced industrially by the reaction of acetic acid and acetylene or acetic acid and ethylene over a suitable catalyst) using an acid or metal catalyst. See, for example, EP0376075A2 a nd S. K. Ka rmee, J. Oil Palm Res. , 2012, 1518-1523.
  • Vinyl esters of the formula (IIA-1) may also be prepa red by the addition a carboxylic acid to a terminal acetylene in the presence of a catalyst (usually a pa lladium or ruthenium complex).
  • a catalyst usually a pa lladium or ruthenium complex.
  • Non-terminal acetylenes may also be reacted . See, for example, N .
  • Lipid conta ining conj ugation partner compounds of the formula (IIB-1) may be prepared in a n analogous fashion, where the compounds of formula (IIA-1) and (IIB-1) are different.
  • the order in which the lipid-containing conjugation partners and amino acid-comprising conjugation partner, for example a peptide-containing conj ugation pa rtner, and any other components present in the reaction mixture are introduced into the reaction vessel may vary.
  • the reaction may be carried out as a one-pot procedure.
  • the ratio of the lipid-conta ining conjugation pa rtners to amino acid-comprising conjugation partner may vary.
  • the mole ratio of the first lipid-containing conjugation partner and second lipid-containing conjugation partner combined (i.e. in total) to the amino acid-comprising conj ugation partner is at least 7 : 1, for example 8: 1, 9: 1, 10: 1, 20 : 1, 30 : 1, 40: 1, 50: 1, 60 : 1, or 70 : 1.
  • the reaction may be carried out at a ny suitable temperature. In some embodiments, the reaction is carried out at a temperature from about -25 °C to about 200 °C, from about - 10 °C to about 150 °C, from about 0 °C to about 125 °C, from about a mbient temperature to about 100 °C. In some embodiments, the reaction is carried out at a temperature of less than about 200 °C, less than about 175 °C, less than about 150 °C, less than about 125 °C, or less than about 100 °C.
  • the reaction is carried out at a temperature above ambient temperature. In one embodiment, the reaction is carried out at a temperature from 40 to 200 °C, from 50 to 150 °C, from 60 to 100 °C, from 65 to 90 °C, or from 70 to 80 °C. In some embod iments, the reaction is carried out at a temperature greater than 40 °C, greater tha n 50 °C, greater tha n 75 °C, greater than 100 °C, or greater tha n 150 °C.
  • the temperature at which the reaction is carried out may depend on how free radicals are generated in the reaction.
  • the temperature used may be selected to control the rate of the reaction.
  • the temperature may be adjusted during the course of the reaction to control the rate of the reaction.
  • the reaction will generally be carried out at a temperature above ambient temperature. The temperature will depend on the reactivity of the species from which free radicals are generated.
  • the reaction may be carried out, advantageously, at ambient temperature. In certain embodiments, it may be desirable to cool the reaction mixture to slow the rate of reaction or conversely heat the reaction mixture to increase the rate of reaction.
  • the temperature at which the reaction is carried out may be controlled by heating or cooling the reaction mixture by suitable method known in the art. Heat may be applied to the reaction mixture, for example, using a heat excha nger within the reaction vessel, a heating jacket surrounding the reaction vessel, or by immersing the reaction vessel in a heated liquid (e.g . an oil or sand bath). In certain exemplary embodiments, the reaction mixture is heated by microwave irradiation.
  • the progress of the reaction may be monitored by a ny suitable means, for example, by thin layer chromatography (TLC) or hig h performance liquid chromatorgraphy (HPLC).
  • the reaction may be allowed to proceed to substantial completion, as monitored by the consumption of at least one of the starting materials.
  • the reaction is a llowed to proceed for a period of time from 1 minute to 7 days, 5 minutes to 72 hours, 10 minutes to 48 hours, 10 minutes to 24 hours.
  • the reaction is a llowed to proceed for a period of time less than 72 h, less than 48 h, less than 24 h, less than 12 h, less than 6 h, less than 4 h, less than 2 h, or less than 1 h.
  • the reaction is carried out until at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99% of the amino acid-comprising conjugation partner has been consumed.
  • the consumption of starting materials may be monitored by any suitable method, for example, HPLC.
  • the reaction mixture may be mixed by a ny suitable method known in the art, for example, using a magnetic or mechanical stirrer.
  • the method used may depend on the scale on which the reaction is carried out.
  • the reaction is generally carried out in a liquid reaction medium.
  • the liquid reaction medium may comprise a solvent.
  • suitable solvents include N- methylpyrrolidone (NMP), dimethylformamide, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, water, methanol, etha nol, dimethylsulfoxide, trifluoroacetic acid, acetic acid, acetonitrile, a nd mixtures thereof.
  • the solvent may be selected based on the solubility of the starting materia ls and other reactants present, for example the free radical initiator.
  • the lipid- containing conjugation partners a re hydrophobic.
  • the hydrophobicity or hydrophilicity of an amino acid-comprising conj ugation partner may va ry depending on, for example, the amino acid seq uence of the peptide of a peptide-containing conj ugation partner.
  • the presence of a solubilising group in the peptide-containing conjugation partner may increase solubility in polar solvents, such as water. A person skilled in the art will be able to select an appropriate solvent without undue experimentation.
  • the reaction may be carried out under substantially oxygen-free conditions.
  • Oxygen may quench free radica ls formed in the reaction.
  • the reaction mixture may be degassed with an inert gas (e.g . nitrogen or argon) that is substantially oxygen-free to remove any dissolved oxygen before free radica ls are generated .
  • an inert gas e.g . nitrogen or argon
  • individua l components of the reaction mixture may be degassed with inert gas that is substantially oxygen-free prior to being combined in the reaction vessel.
  • the reaction may be carried out under a n atmosphere of inert gas that is substantially oxygen-free.
  • the method of the present invention may be carried out at ambient pressure.
  • An additive that inhibits the formation of undesireable by-prod ucts and/or that improves the yield of or conversion to the desired product may be included in the reaction mixture in the thiolene method of the present invention.
  • the one or more additive may be a n extraneous thiol, a n acid, an organosilane, or a combination of any two or more thereof.
  • an extraneous or exogenous thiol as an additive in the reaction mixture reduces the formation of undesirable by products.
  • the extraneous thiol may, in some embodiments, increase the efficiency or conversion of the desired thiolene reaction.
  • suitable extraneous thiols include but are not limited to reduced glutathione, DODT, DTT, protein, sterically hindered thiols, and the like.
  • the extraneous thiol is DTT.
  • the extraneous thiol is a sterically hindered thiol.
  • a suitable sterically hindered extra neous thiol include terf-butyl mercaptan and 1-methylpropyl mercaptan.
  • an extraneous thiol such as terf-butylmercaptan can provide a proton to quench the radical intermed iate formed on propogation of the rad ical of formula (X) with the alkene of formula (IIB) to provide the desired compound of formula (IB) and the resulting thiyl rad ical can propagate the reaction by generating another mole of thiyl radical from the amino acid comprising conjugation pa rtner of formula (III).
  • extraneous thiols may in certain embodiments also be capable of prematurely quenching the reaction by providing a proton radical of formula (X).
  • the extraneous thiol and the amount in which it is used may be selected such that the yield of or conversion to (as determined by HPLC) the compound of formula (IB) is optimised.
  • the extraneous thiol is present in the reaction in a
  • a sterically hindered thiol such as t-BuSH is present in the reaction in a stoichiometric ratio relative to the amino acid comprising conjugation partner of from about 100:1 to 0.05:1, for example about 80:1, about 40:1, or about 3:1.
  • an acid in some embodiments may also reduce the formation of undesireable by-products.
  • the acid may be a strong inorganic acid, for example HCI, or organic acid, for example TFA.
  • the additive is TFA.
  • the reaction mixture comprises from about 0.01 to 25, 0.01 to 15, 0.01 to 10, or 1 to 10% v/v acid additive.
  • the reaction mixture comprises from 1-10% v/v TFA, for example 5% v/v TFA.
  • the reaction mixture comprises a combination of an acid and an exogenous thiol, such as a combination of a strong organic acid and a sterically hindered thiol, for example a combination of TFA and terf-butyl mercaptan.
  • An organosilane may also be included as an additive in the thiolene reaction.
  • Organosilanes are radical-based reducing agents, the activity of which can be modulated by varying the substituents on the silicon atom.
  • the organosilane is a compound of the formula (R q )3SiH, wherein Rq at each instance is independently hydrogen or an organic group, for example alkyl or aryl, provided that at least one Rq is not hydrogen.
  • organosilanes include but are not limited to triethylsilane (TES), triphenylsilane, diphenylsilane, triisopropylsilane (TIPS), and the like.
  • the organosilane is a trialkylsilane, for example TIPS or TES.
  • an organosilane such as TIPS can act as a hydrogen donor to provide the desired compound of formula (IB) and promote propagation of the reaction.
  • the organosilane is present in the reaction in a stoichiometric ratio relative to the amino acid comprising conjugation partner of from about 200:1 to about 0.05:1, 100:1 to 0.05:1, 80:1 to 0.05:1, 60:1 to 0.05:1, 40:1 to 0.05:1, 20:1 to 0.05:1, 10:1 to 0.5:1, 5:1 to about 1:1, or 3:1 to about 1:1.
  • a trialkylsilane such as TIPS is present in the reaction in a stoichiometric ratio relative to the amino acid comprising conjugation partner of from about 100:1 to 0.05:1, for example about 80:1 or about 40:1.
  • the organosilane may be used as an additive in combination with an extraneous thiol.
  • the organosilane may be used instead of an extraneous thiol.
  • An acid, such as TFA, may also be present.
  • embodiments using TIPS in the reaction together with TFA but without any extraneous thiol can provide higher conversion to the desired compound of formula (IB) than when a combination of TIPS, t-BuSH, and TFA are used.
  • the additive is generally used in an amount sufficient to minimise the formation of undesirable by products without adversely affecting the reaction or any, optional, subsequent steps in the method.
  • the products formed in the reaction and conversion to the desired product may be determined by, for example, HPLC.
  • the concentration of the lipid-containing conjugation partners and amino acid-compirsing conjugation partner, for example a peptide-containing conjugation partner, respectively, in the reaction mixture may also affect the reaction.
  • concentration of the lipid-containing conjugation partners and peptide- containing conjugation partner in the reaction mixture may be varied to e.g. optimise yield and purity without undue experimentation.
  • the starting material comprising the thiol is present in a concentration from about 0.05 mM to about 1 M, from about 0.5 mM to about 1 M, from about 1 mM to about 1 M . In some embodiments, the concentration is at least about 0.05 mM, 0.5 mM, or 1 mM .
  • the concentration of the starting materials comprising the alkenes is at least about 0.05 mM, 0.5 mM, or 1 mM .
  • the amino acid conj ugate or peptide conj ugate is separated from the reaction med ium after the reaction a nd optionally purified.
  • the conjugate may be separated from the reaction medium using any suitable method known in the art, for example, by precipitation.
  • the amino acid or peptide conjugate is purified after separating it from the reaction med ium.
  • the conjugate may be purified by HPLC using one or more suitable solvents.
  • the present invention also provides a method of making a peptide conjugate, the method comprising
  • the peptide conjugate produced by and/or the peptide-conta ining conjugation partner and/or the peptides coupled in the methods of the present invention may comprise a synthetic peptide.
  • Synthetic peptides may be prepa red using solid phase peptide synthesis (SPPS).
  • SPPS solid phase peptide synthesis
  • the amino acid to be coupled to the resin is protected at its Na-terminus by a chemical protecting group.
  • the amino acid may also have a side-chain protecting group.
  • Such protecting groups prevent undesired or deleterious reactions from taking place during the process of forming the new peptide bond between the carboxyl g roup of the amino acid to be coupled a nd the unprotected Na-amino g roup of the peptide cha in attached to the resin.
  • the amino acid to be coupled is reacted with the unprotected Na-amino group of the N- termina l amino acid of the peptide chain, increasing the chain length of the peptide chain by one amino acid .
  • the carboxyl group of the amino acid to be coupled may be activated with a suitable chemical activating agent to promote reaction with the ⁇ -amino group of the peptide chain.
  • the Na-protecting group of N-terminal amino acid of the peptide chain is then removed in preparation for coupling with the next amino acid residue.
  • This techniq ue consists of many repetitive steps making a utomation attractive whenever possible.
  • peptides may be coupled to the Na- amino group of the solid phase bound amino acid or peptide instead of an individ ua l amino acid, for example where a convergent peptide synthesis is desired .
  • the peptide is cleaved from the solid phase support at the linker molecule.
  • SPPS may be carried out using a continuous flow method or a batch flow method .
  • spectrophotometer but has two distinct disadvantages - the reagents in contact with the peptide on the resin are diluted, a nd scale is more limited due to physical size constraints of the solid phase resin. Batch flow occurs in a filter reaction vessel and is useful because reactants are accessible and ca n be added manually or automatically.
  • Two types of protecting groups are commonly used for protecting the N-alpha-amino terminus: "Boc” (terf-butyloxycarbonyl) and “Fmoc” (9-fluorenylmethyloxycarbonyl) .
  • Reagents for the Boc method are relatively inexpensive, but they are highly corrosive and require expensive equipment and more rigorous precautions to be taken.
  • the Fmoc method which uses less corrosive, although more expensive, reagents is typically preferred .
  • the solid phase support used for synthesis can be a synthetic resin, a synthetic polymer film or a silicon or silicate surface (e.g . controlled pore glass) suitable for synthesis purposes.
  • a resin is used, commonly polystyrene suspensions, or polystyrene-polyethyleneglycol, or polymer supports for example polyamide.
  • linkers suitable for Boc-chemistry include PAM resin, oxime resin SS, phenol resin, brominated Wang resin and brominated PPOA resin.
  • resins suitable for Fmoc chemistry include amino-methyl polystyrene resins, AMPB-BHA resin, Sieber amide resin, Rink acid resin, Tentagel S AC resin, 2-chlorotrityl chloride resin, 2-chlorotrityl alcohol resin, TentaGel S Trt-OH resin, Knorr-2-chlorotrityl resin, hydrazine-2-chlorotrityl resin, ANP resin, Fmoc photolable resin, HM BA-M BHA resin, TentaGel S HM B resin, Aromatic Safety Catch resinBAI resin and Fmoc-hydroxylamine 2 chlorotrityl resin.
  • Other resins include PL Cl-Trt resin, PL-Oxime resin and PL-HM BA Resin. Genera lly resins are interchangeable.
  • Preparation of the solid phase support includes solvating the support in an appropriate solvent (e.g. dimethylformamide).
  • an appropriate solvent e.g. dimethylformamide.
  • the solid phase typically increases in volume during solvation, which in turn increases the surface area ava ilable to carry out peptide synthesis.
  • Linker molecules are then attached to the support for connecting the peptide chain to the solid phase support.
  • Linker molecules are generally desig ned such that eventual cleavage provides either a free acid or amide at the C-terminus.
  • Linkers are generally not resin- specific. Examples of linkers include peptide acids for example 4- hydroxymethylphenoxyacetyl-4'-methylbenzyhydrylamine (HMP), or peptide amides for example benzhydrylamine derivatives.
  • HMP 4- hydroxymethylphenoxyacetyl-4'-methylbenzyhydrylamine
  • peptide amides for example benzhydrylamine derivatives.
  • the first amino acid of the peptide sequence may be attached to the linker after the linker is attached to the solid phase support or attached to the solid phase support using a linker that includes the first amino acid of the peptide sequence.
  • Linkers that include amino acids are commercially ava ilable.
  • the next step is to deprotect the Na-amino group of the first amino acid .
  • deprotection of the ⁇ -amino group may be ca rried out with a mild base treatment (piperazine or piperidine, for example). Side-chain protecting groups may be removed by moderate acidolysis (trifluoroacetic acid (TFA), for example).
  • TFA trifluoroacetic acid
  • deprotection of the ⁇ -amino group may be ca rried out using for example TFA.
  • the amino acid chain extension, or coupling proceeds by the formation of peptide bonds.
  • This process requires activation of the C-a-carboxyl group of the amino acid to be coupled .
  • This may be accomplished using, for example, in situ reagents, preformed symmetrical anhydrides, active esters, acid halides, or urethane- protected N-carboxyanhydrides.
  • the in situ method allows concurrent activation and coupling .
  • Coupling reagents include carbodiimide derivatives, for example ⁇ , ⁇ '- dicyclohexylcarbod iimide or ⁇ , ⁇ -diisopropylcarbodiimide.
  • Coupling reagents also include uronium or phosphonium salt derivatives of benzotriazol.
  • uronium and phosphonium salts include HBTU (0-lH-benzotriazole-l-yl)-N,N,N',N '- tetramethyluronium hexafluorophosphate), BOP (benzotriazole-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-l-yl-oxy- tripyrrolidinophosphonium hexafluorophosphate), PyAOP, HCTU (0-(l H-6-chloro- benzotriazole-l-yl)-l, l,3,3-tetramethyluronium hexafluorophosphate), TCTU (0-1H-6- chlorobenzotriazole-l-yl)-l, l,3,3-

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