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CN-121985966-A - Stealth stable sulfur-containing lipid/polyamino acids

CN121985966ACN 121985966 ACN121985966 ACN 121985966ACN-121985966-A

Abstract

The present invention relates to sulfur-containing lipid-polyamino acid conjugates of formula (I) and acceptable salts, stereoisomers and mixtures thereof. The invention also relates to self-assembled particles comprising these lipid/polyamino acid conjugates and optionally an active agent, and to compositions comprising the lipid-polyamino acid conjugates or self-assembled particles comprising them. The invention also relates to the use of lipid-polyamino acid conjugates, self-assembled particles or compositions comprising them in medicine, cosmetics and diagnostics, and to the use of lipid-polyamino acid conjugates of formula (I) as carriers.

Inventors

  • T. J. Deming
  • C. Philippe Leon
  • J. Garcia Garcia Garcia
  • V. J. Nebotekada
  • L. Herrera Munoz

Assignees

  • 多肽治疗解决公司
  • 加利福尼亚大学董事会

Dates

Publication Date
20260505
Application Date
20240802
Priority Date
20230804

Claims (15)

  1. 1. Lipid-polyamino acid conjugates of formula (I), salts thereof, or any stereoisomers or mixtures of stereoisomers of compounds of formula (I) or any salts thereof, Wherein, the PAA 1 is a repeating unit of formula (II) PAA 2 is a repeating unit of formula (III) Wherein, although the repeating units PAA 1 and PAA 2 are shown in a particular order for ease of description, the repeating units may be present in any order and may be block or random, and wherein each of the repeating units PAA 1 and PAA 2 may comprise blocks of monomers that may be the same or different from each other; n is an integer from 5 to 250; m is an integer from 0 to 250; p is 0 or 1; s is 0 or 1; x is selected from the group consisting of CH, N, S, and O; x' is selected from the group consisting of N and O; R 1 and R 1 ' are independently selected from the group consisting of H, - (C 1 -C 18 ) alkyl and- (C 2 -C 18 ) alkenyl, provided that R 1 is absent when X is O or S, and R 1 ' is absent when X ' is O; r 2 is a radical selected from the group consisting of (IV), (V) and (VI) Wherein a, b and C are each independently integers from 0 to 3; R is- (C 1 -C 6 ) alkyl, R' is selected from the group consisting of- (C 1 -C 6 ) alkyl-SO 3 -and- (C 1 -C 6 ) alkyl-CO 2 -; R 3 and R 5 are each independently selected from the group consisting of H and- (C 1 -C 6 ) alkyl; R 4 is any amino acid side chain, optionally functionalized with an active moiety; A is selected from the group consisting of H, - (C 1 -C 6 ) alkyl, -CO (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl-CO-N [ (C 1 -C 18 ) alkyl ] 2 、-(C 5 -C 10 ) aryl, - (C 5 -C 10 ) heteroaryl, - (C 6 -C 10 ) aralkyl, - (C 1 -C 6 ) alkyl-O- (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heterocycloalkyl, free radical (IV), free radical (V), free radical (VI), protecting group, lipid-like moiety R 7 and active moiety; A 1 is selected from the group consisting of H, -OH, - (C 1 -C 6 ) alkyl, - (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heteroaryl, - (C 6 -C 10 ) aralkyl, - (C 1 -C 6 ) alkyl-O- (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heterocycloalkyl, - (C 1 -C 10 ) alkoxy, - (C 6 -C 10 ) aryloxy, - (C 6 -C 10 ) aralkoxy, - (C 5 -C 10 ) heteroaralkoxy, - (C 1 -C 10 ) alkyl-O- (C 6 -C 10 ) aryloxy, amino protecting group, lipid-like moiety R 7 ', amino acid-like moiety R 8 , and active moiety; The conditions are as follows: i) When p is 0, s is 0 and A 1 is selected from the group consisting of H, - (C 1 -C 6 ) alkyl, - (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heteroaryl, - (C 6 -C 10 ) aralkyl, - (C 1 -C 6 ) alkyl-O- (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heterocycloalkyl, amino protecting group, lipid-like moiety R 7 ', amino-acid-like moiety R 8 and active moiety; ii) when p is 1 and s is 0, A 1 is selected from the group consisting of H, -OH, - (C 1 -C 6 ) alkyl, - (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heteroaryl, - (C 6 -C 10 ) aralkyl, - (C 1 -C 6 ) alkyl-O- (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heterocycloalkyl, - (C 1 -C 10 ) alkoxy, - (C 6 -C 10 ) aryloxy, - (C 6 -C 10 ) aralkoxy, - (C 5 -C 10 ) heteroaralkoxy, - (C 1 -C 10 ) alkyl-O- (C 6 -C 10 ) aryloxy, lipid-like moiety R 7 ' and active moiety; iii) When p is 1 and s is 1, A 1 is selected from the group consisting of H, - (C 1 -C 6 ) alkyl, - (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heteroaryl, - (C 6 -C 10 ) aralkyl, - (C 1 -C 6 ) alkyl-O- (C 5 -C 10 ) aryl, - (C 5 -C 10 ) heterocycloalkyl, - (C 1 -C 10 ) alkoxy, - (C 6 -C 10 ) aryloxy, - (C 6 -C 10 ) aralkoxy, - (C 5 -C 10 ) heteroaralkoxy, - (C 1 -C 10 ) alkyl-O- (C 6 -C 10 ) aryloxy, lipid-like moiety R 7 ' and active moiety, and Iv) at least one of a and a 1 is a lipid-like moiety R 7 or R 7 '; v) when A 1 is H, s is 0, p is 0, X is N, R 1 is H, then A is not butyl; vi) when A 1 is H, p is 0, s is 0, X is N and A is H, then R 1 is not butyl, and Vii) when a is methyl, X is N, R 1 is H, p is 1 and s is 0, then a 1 is not a lipid-like moiety R 7 of formula (XVII) wherein each j is 16, i is 2; Wherein a and a 1 are independently optionally substituted with one or more groups selected from the group consisting of: -OH, halogen, -CF 3 、-NH 2 、-NH-(C 1 -C 4 ) alkyl, -NH-CO- (C 1 -C 6 ) alkyl, - (C 1 -C 6 ) alkyl, -NO 2 、-N 3 、-CO-(C 1 -C 6 ) alkyl, -CO-O- (C 1 -C 6 ) alkyl, -SO 3 H、-SO 2 NH 2 、-SO 2 -N((C 1 -C 6 ) alkyl) 2 、-COOH、CONH 2 、-(CH 2 ) 2 -SO-CH 3 、-CON((C 1 -C 6 ) alkyl) 2 and NH (C 1 -C 6 ) alkyl; Each lipid-like moiety R 7 is independently selected from the group consisting of- (C 1 -C 20 ) alkyl, - (C 2 -C 20 ) alkenyl, and a free radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII) or (XVIII) Each R 7 'is independently selected from the group consisting of- (C 1 -C 20 ) alkyl, - (C 2 -C 20 ) alkenyl and a radical of formula (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII) or (XVIII') Wherein: Y and Y' are independently selected from the group consisting of-OH, -OCORx and-COORx; q and Q' are independently selected from-OCORy and-COORy; z and Z ' are independently selected from the group consisting of-O-, -OCO-, -COO-, -NRz ' CO-and-CONRz ' -; Each Rz' is H or Rz; Each Rx, ry and Rz is independently- (C 1 -C 18 ) alkyl or- (C 2 -C 18 ) alkenyl; each g is independently an integer from 0 to 18; each h is independently an integer from 1 to 18; i is an integer from 0 to 18; Each j is independently an integer from 0 to 18; t is 0 or 1, provided that t is 0 when x=o and t is 1 when X is not O; t ' is 0 or 1, provided that t ' =1 when p is 0 and s is 0, and t ' =1 when p is 1 and s is 1; R 22 、R 33 and R 44 are independently selected from the group consisting of hydrogen, fluoro, methyl, -CH 2 F、-CHF 2 , and-CF 3 ; each dashed bond is independently a single bond or alternatively a double bond; L is a diradical chain comprising one or more moieties ：-CH=CH-、-C≡C-、-CH 2 -、-N=CH-、-CH=NH-、-NH-、-NH-NH-、-NH-N=CH-、-O-、-O(CH 2 )O-、-CO-、-O(CO)-、-(CO)O-、-C(=CH 2 )-、-C(=NH)-、-CONH-、-NHCO-、NH(CO)NH-、-S-、-S-S-、-SO-、-SO 2 -、-SO 2 NH 2 - selected from the group consisting of and-phenylene-, wherein L is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NR a R b 、-SH、-NHNH 2 、-COOR c 、-CF 3 、-OCF 3 , Wherein when L comprises a-CH 2 -moiety, the two hydrogen atoms attached to the carbon atom are optionally replaced with rings: And is also provided with Each R 8 is a radical independently selected from the group consisting of (XX), (XXI) and (XXII) Wherein each a ', each b ', and each C ' are independently integers from 0 to 3, each R 9 is independently- (C 1 -C 6 ) alkyl, and R 10 is selected from the group consisting of- (C 1 -C 6 ) alkyl-SO 3 -and- (C 1 -C 6 ) alkyl-CO 2 -; “ "means attachment point, and Each active moiety is independently selected from the group consisting of a pharmaceutically active agent, a permeation enhancer, a cell targeting agent, a cosmetically active agent, and a diagnostically active agent.
  2. 2. The lipid-polyamino acid conjugate according to claim 1 having the formula (IA) 。
  3. 3. The lipid-polyamino acid conjugate according to any one of claims 1 to 2, wherein n is an integer from 5 to 100.
  4. 4. A lipid-polyamino acid conjugate according to any of claims 1 to 3 wherein R 3 is H.
  5. 5. The lipid-polyamino acid conjugate according to any of claims 1 to 4, wherein X is N and R 1 is selected from the group consisting of H and- (C 1 -C 6 ) alkyl.
  6. 6. The lipid-polyamino acid conjugate according to any of claims 1 to 5, wherein R 7 is selected from the group consisting of- (C 1 -C 20 ) alkyl, - (C 2 -C 20 ) alkenyl and radicals of formula (XI), (XII), (XIV), (XV), (XVI), (XVII) or (XVIII), and R 7 'is selected from the group consisting of- (C 1 -C 20 ) alkyl, - (C 2 -C 20 ) alkenyl and radicals of formula (XI), (XII), (XIV), (XV), (XXVI), (XVII) or (XVIII').
  7. 7. The lipid-polyamino acid conjugate according to any one of claims 1 to 6, wherein a is a lipid-like moiety R 7 and a 1 is not a lipid-like moiety R 7 '.
  8. 8. The lipid-polyamino acid conjugate according to any one of claims 1 to 6, wherein a 1 is a lipid-like moiety R 7 ' and a is not a lipid-like moiety R 7 .
  9. 9. A self-assembled particle comprising a lipid-polyamino acid conjugate of formula (I) according to any one of claims 1 to 8 and optionally one or more active agents selected from the group consisting of pharmaceutically active agents, cell targeting agents, permeation enhancers, cosmetically active agents, diagnostic active agents, nucleic acids, peptides, proteins and mixtures thereof.
  10. 10. A composition comprising a lipid-polyamino acid conjugate of formula (I) according to any one of claims 1 to 8 or, alternatively, a self-assembled particle according to claim 9, together with one or more suitable excipients or carriers.
  11. 11. A therapeutic product for medical use, comprising: a) The lipid-polyamino acid conjugate of formula (I) according to claim 1 to 8 wherein at least one of A, A 1 、A 2 or A 3 is a pharmaceutically active agent, or alternatively B) Self-assembled particles according to claim 9 comprising the lipid-polyamino acid conjugate a), or alternatively C) The composition according to claim 10 comprising the lipid-polyamino acid conjugate a) or the self-assembled particle b), or alternatively D) The self-assembled particle of claim 9 comprising one or more active agents selected from the group consisting of pharmaceutically active agents, nucleic acids, peptides, proteins, and mixtures thereof, or alternatively, E) The composition of claim 10, comprising the self-assembled particle d).
  12. 12. The therapeutic product for use according to claim 11 for (i) transfection of at least one active agent into cells as a transfection reagent, (ii) for in vivo or ex vivo production of a biological product encoding a recombinant protein, peptide or antibody, or for production of a recombinant virus, (iii) as a therapeutic or prophylactic vaccine against an anti-viral infection, or a therapeutic vaccine against cancer or an infectious disease, or (v) for genome engineering, cell reprogramming, cell differentiation or gene editing.
  13. 13. A diagnostic product for diagnostic use, comprising: a') a lipid-polyamino acid conjugate of formula (I) according to any of claims 1 to 8, wherein at least one of A, A 1 、A 2 or A 3 is a diagnostic active agent, or alternatively, B ') the self-assembled particle according to claim 9 comprising said lipid-polyamino acid conjugate a'), or alternatively, C ') the composition according to claim 10 comprising the lipid-polyamino acid conjugate a ') or the self-assembled particle b '), or alternatively, D') the self-assembled particle according to claim 9, comprising one or more diagnostic active agents, or alternatively, E ') the composition according to claim 10 comprising said self-assembled particles d').
  14. 14. Cosmetic use of a cosmetic product comprising: a ") the lipid-polyamino acid conjugate of formula (I) according to any of claims 1 to 8, wherein at least one of A, A 1 、A 2 or A 3 is a cosmetically active agent, or alternatively, B ") the self-assembled particle according to claim 9 comprising the lipid-polyamino acid conjugate a"); or alternatively, the number of the cells may be, C ") the composition according to claim 10 comprising the lipid-polyamino acid conjugate a") or the self-assembled particle b "), or alternatively, D ") the self-assembled particle according to claim 9, comprising one or more cosmetically active agents, or alternatively, E ") the composition according to claim 10 comprising self-assembled particles d").
  15. 15. Lipid-polyamino acid conjugate of formula (I) according to any of claims 1 to 8, wherein A, A 1 、A 2 and a 3 are not active moieties or, alternatively, self-assembled particles according to claim 9 containing the conjugate, are used as carriers.

Description

Stealth stable sulfur-containing lipid/polyamino acids The present application claims the benefit of european patent application EP23382821.9 filed on month 8 and 4 of 2023. Technical Field The present disclosure relates to lipid-polyamino acid conjugates comprising a sulfur-containing polyamino acid (PAA) moiety conjugated to a lipid-like moiety. These lipid-polyamino acid conjugates can form self-assembled nanoparticles, such as Lipid Nanoparticles (LNPs), and can be used as non-viral vectors for delivering active ingredients, including nucleic acids, to cells. Background In recent years, nucleic acids have emerged as promising drug candidates for the generation of a variety of diseases including cancer, infectious diseases, and cardiovascular, inflammatory and neurodegenerative diseases, among others. Nucleic acids function by gene suppression, addition, substitution, or editing. However, their clinical efficacy is very limited because they cannot penetrate the physiological barrier. The negative charge and hydrophilicity of nucleic acids prevent their passive diffusion across the plasma membrane. Furthermore, the binding of nucleic acids to serum proteins and their susceptibility to enzymatic degradation by endogenous nucleases also interfere with their efficient conversion to functional reactions. Non-viral vectors such as LNP are known to penetrate the plasma membrane and thus are capable of delivering nucleic acids to cells. LNP are vesicles composed of a mixture of lipids that physically associate with each other by intermolecular forces to form a micelle structure. LNPs typically have small diameters of less than 200 nm. LNP is used as a drug delivery system because it is capable of encapsulating a bioactive agent and delivering it to a specific location within the body within a desired time. The lipid component of LNP can include ionizable or cationic lipids, helper lipids (e.g., phospholipids) and structural lipids (e.g., sterols or cholesterol). Ionizable/cationic lipids have a permanent or ionizable positively charged head group followed by a hydrophobic tail, which can form complexes with negatively charged nucleic acids via electrostatic bonds. One of the potential problems with LNP is that once injected, they may be recognized by the immune system as foreign particles, which are subsequently cleared from the blood stream by phagocytes. To overcome this problem, different strategies may be used, including reducing the particle size of the vesicles or modifying their surface. For example, the LNP surface can be modified by conjugating a hydrophilic polymer polyethylene glycol (PEG) to a lipid (e.g., a phospholipid or long chain fatty acid) to form a PEG-lipid. PEG is a hydrophilic polymer that is widely used for drug delivery and nanotechnology due to its stealth properties and biocompatibility. By virtue of these properties, the PEG-containing particle delivery system is able to evade the immune system, thus achieving longer circulation times in vivo. Nevertheless, it has recently been reported that the presence of covalently bonded PEG also significantly reduces transfection efficiency, as the neutral surface of nanoparticles can reduce cell uptake efficiency. In addition, PEG is known to also produce anti-PEG antibodies that may elicit immunogenicity and allergic reactions. Although other hydrophilic polymers such as poly (vinyl pyrrolidone), poly (acryloyl-morpholine) or polyoxazoline have been reported as alternatives to PEG lipids, no LNP containing such polymers has been marketed at present. Polysarcosine (pSar) is a polypeptide based on the endogenous amino acid sarcosine (N-methylated glycine), which has previously shown potent stealth properties. The therapeutic use of Lipid Nanoparticles (LNP) for messenger RNAs assembled using polymorphylated lipids has been reported as a promising particle engineering tool (ACS appl. Nano mate, 2020, 3, 10634-10645), but this technology is still under development and no clinical data for incorporating such polymers into LNP is currently available. Thus, based on the current state of the art knowledge, there remains a need to develop alternative LNPs that overcome the deficiencies of the prior art. Disclosure of Invention The inventors have developed new lipid-polyamino acid conjugates comprising a sulfur-containing polyamino acid (PAA) moiety conjugated to at least one lipid-like moiety. These conjugates can form self-assembled nanoparticles, such as Lipid Nanoparticles (LNPs), and can be effectively used as non-viral vectors for delivering active ingredients, including nucleic acids, to cells due to their stealth properties and subsequently improved plasma half-life. In addition, the sulfur-containing lipid-polyamino acid conjugates exhibit low cytotoxicity and high biodegradability and can confer enhanced efficiency and high stability to the final nanosystems due to limited or even completely inhibited aggregation problems in the blood stream an