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Glycopeptide vaccine

A peptide antigen, compound technology, applied in the field of vaccines to prevent or reduce the incidence of malaria in subjects, can solve problems such as low efficacy

Pending Publication Date: 2022-05-27
VICTORIA LINK LTD +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While Mosquirix is ​​considered the most advanced vaccine candidate in trials, it requires four injections and has relatively low efficacy

Method used

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  • Glycopeptide vaccine
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0337] Example 1 - Synthesis of Peptides for Conjugation

[0338] 5-azidovaleryl-FFRK-AAAHSLSNVYDFNLLLERD (SEQ ID NO: 1-SEQ ID NO: 3)

[0339] 5-azidovaleryl-FFRK-AAAHSLSNVYDFNLLLERD (SEQ ID NO: 1 - SEQ ID NO: 3) by FmocSPPS in 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB) Synthesis on resin preloaded with Fmoc-L-aspartate 4-tert-butyl ester (Fmoc-Asp(tBu)) as the first amino acid. Alpha-amino acids with the following side chain protecting groups were used: Arg(Pbf), Lys(Boc), Ser(tBu), Asn(Trt), His(Trt), Tyr(tBu), Asp(tBu), Glu(tBu) ), and use Initiator+Alstra TMThe microwave peptide synthesizer synthesizes peptides on a 0.1 mmol scale. The resin was swollen in DMF (20 min, 70° C., 50 W), followed by a synthetic reaction cycle consisting of: Fmoc deprotection with 20% piperidine in DMF (3 min, then 10 min, room temperature); and amino acid coupling (5 min, 75°C, 50W) using 5 equiv of the protected amino acid (0.5M) in DMF via 5 equiv of diisopropylcarbodiimi...

Embodiment 2

[0345] Example 2: Synthesis of glycolipid-linker for oxime conjugation

[0346] 4-(N-((9H-Fluoren-9-yl)methoxycarbonyl)-L-valyl-L-citrullineamido)benzyl 4-nitrophenylcarbonate (Fmoc-VCPAB- pNP)

[0347]

[0348] To a mixture of the alcohol Fmoc-VC-PABOH (Dubowchik, 2002) (400 mg, 0.665 mmol) in DMF (6.0 mL) was added bis(4-nitrophenyl)carbonate (255 mg, 0.796 mmol) and i-Pr 2 NEt (0.13 mL, 0.75 mmol). After stirring under Ar at room temperature for 18 h, the solvent was co-evaporated several times with toluene in a rotary evaporator. Flash chromatography on silica gel (gradient elution, MeOH / CHCl 3 = 0:100 to 8:92) to give the title compound as a pale yellow solid (380 mg, 75%). 1 H NMR (500MHz, d 6 -DMSO)δ0.85(d,J=6.7Hz,3H),0.88(d,J=6.7Hz,3H),1.33-1.49(m,2H),1.56-1.64(m,1H),1.67-1.74 (m,1H),1.95-2.02(m,1H),2.91-2.97(m,1H),2.99-3.06(m,1H),3.92(dd,J=7.2,8.7Hz,1H),4.20-4.26 (m,2H),4.28-4.33(m,1H),4.39-4.43(m,1H),5.24(s,2H),5.39(br s,2H),5.98(br t,J=5.7Hz,1H ), 7.30-7....

Embodiment 3

[0358] Example 3: Synthesis of glycolipid-peptide conjugates

[0359] SPAAC conjugate vaccine

[0360] MaGC-PAB-CV-cyclooctyne and conjugate compound V.S.FFRK.OVA were synthesized as previously described LP (C 26 ). (Anderson RJ, 2017)

[0361]

[0362] Conjugate V.S.FFRK.NVY SP

[0363]

[0364] 5-azidovaleryl-FFRK-NVYDFNLL (SEQ ID NO: 1-SEQ ID NO: 2) (1.6 mg, 0.96 μmol) and MaGC-PABA-CV-cyclooctyne (1.0 mg, 0.69 μmol) were added The solution in DMSO (100 μL) was kept at room temperature for 2 days. The product solution was passed through semi-preparative HPLC (Phenomenex Luna C18(1), 4.6 μm, 250×10 mm, 40°C, mobile phase A=100:0.05 water / TFA; mobile phase B=100:0.05MeOH / TFA; gradient program : T0=80%B, T12=100%B, T14=100%B, T14.5=80%B, T16=80%B; flow rate: T0=3mL / min, T1=3mL / min, T12=4.5 mL / min, T14=4.5mL / min, T16=3mL / min), get V.S.FFRK.NVY SP , as a white powder (1.8 mg, 82%). HRMS-ESI m / z calculation C 162 H 257 N 27 O 35 [M+2H] 2+ 1570.4580, measured...

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Abstract

The present invention relates generally to glycopeptide conjugate compounds of Formula I: as described herein, compositions comprising conjugate compounds and the use of such compounds as vaccines.

Description

1. Technical field [0001] The present invention generally relates to glycolipid-peptide conjugates of formula I and the use of these conjugates as vaccines to prevent or reduce the incidence of malaria in a subject. 2. Background technology [0002] Malaria is a highly prevalent parasitic disease, with approximately 216 million people contracting malaria annually in 2016 and more than 445,000 deaths. The disease reduces the gross domestic product of severely affected countries by billions each year and causes severe physical and psychological damage to affected children. [0003] The disease is caused by Plasmodium spp., which is transmitted by female Anopheles mosquitoes. After being bitten by an infected mosquito, immature parasites (sporozoites) injected into the skin circulate through the bloodstream to the liver, where they infect liver cells. Sporozoites mature and replicate within hepatocytes over about a week in humans, or over two days in mice. The sporozoites ar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/445A61K39/015A61P33/06A61K31/7032
CPCA61K39/015A61P33/06A61K31/7032C07K14/445A61K47/646A61K2039/6018A61K2039/627A61K2039/57C07K2319/50C07K2319/40C07K16/2851A61K2039/505A61P31/00A61K47/543A61K47/549A61K2039/6087A61K2039/6056A61K2039/55561C12N2710/16143A61K2039/545
Inventor 戴尔·伊恩·戈德弗里威廉·罗斯·希斯劳伦·爱丽丝·霍尔兹伊恩·弗朗西斯·赫尔曼斯加文·弗兰克·佩因特里根·詹姆斯·安德森本杰明·杰森·康普顿希瓦利·阿什温·古拉布
Owner VICTORIA LINK LTD