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Short and D-amino acid-containing polypeptides for therapeutic conjugates and uses thereof

一种氨基酸、序列的技术，应用在短多肽领域，能够解决削弱大脑疾病治疗等问题

Inactive Publication Date: 2013-05-01
ANGLACHEM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Treatment of brain disorders often impairs due to inability of otherwise potent therapeutic agents to cross the BBB

Method used

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  • Short and D-amino acid-containing polypeptides for therapeutic conjugates and uses thereof
  • Short and D-amino acid-containing polypeptides for therapeutic conjugates and uses thereof
  • Short and D-amino acid-containing polypeptides for therapeutic conjugates and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0461] Synthesis of shorter analogs of Angiopep-2-Cys (P1 to P6)

[0462] Using Fmoc (9-fluorenylmethoxycarbonyl) amino terminal protection, in Protein Technologies, Inc. SPPS (Solid Phase Peptide Synthesis) was performed on a peptide synthesizer. Shorter Angiopeps were synthesized on a 100 micromolar scale using a 5-fold excess of Fmoc-amino acid (200 mM) relative to the resin. Crude peptides were precipitated with ice-cold ether and purified by reverse-phase high-performance liquid chromatography (Waters Delta Prep 4000). Acetonitrile was evaporated from the collected fractions and lyophilized to give a pure white solid (>95% purity). Mass was verified using ESI-TOF MS (Bruker Daltonics). Table 4 lists the sequences of Angiopep-2-Cys (AN2-Cys) and various shorter analogs (P1 to P6).

[0463] Table 4 Shorter analogs of Angiopep-2-Cys (P1 to P6)

[0464]

Embodiment 2

[0466] Transport of shorter analogues P1 and P5

[0467] To confirm that the shorter analogs P1 and P5 crossed the BBB, in situ brain perfusion was performed using standard methods in the art. Measure initial transport as a function of time. The results indicated that the brain uptake for P1 and P5 was similar or higher than that of Angiopep-2 (An2) ( figure 1 ). Capillary depletion can also be performed to quantify the amount of analogues found in the brain parenchyma ( figure 1). Similar or higher levels of P5 were found in the brain parenchyma when compared to An2 and P1. In addition, these results indicate that the analogs are not trapped in brain capillaries. Overall, our findings suggest that the new shorter analogs P1 and P5 efficiently cross the blood-brain barrier.

Embodiment 3

[0469] Characterization of P5 and P6 Neurotensin Derivatives

[0470] Compared to ANG2002 (a modified neurotensin (NT) bound to Angiopep-2 via an EMCS linker) with the following structure, we performed an experiment to test whether the shorter analog could induce analgesia or persistent Hypothermia:

[0471]

[0472] Binders tested included P5-NT with the sequence KRNNFKTEEYC-pELYENKPRRPYIL and P6-NT with the sequence KRNNFKYC-pELYENKPRRPYIL, where both P5 and P6 were bound to the lysine of the NT via an EMCS linker, and pE represents pyro-L-glucose acid.

[0473] To determine the induction of analgesia, we tested the relationship between hot-plate foot exposure and foot-licking behavior in control mice and mice receiving ANG2002, P5-NT, and P6-NT at equal doses of neurotensin. delay. Therefore, mice received a single bolus of 20 mg / kg ANG2002 intravenously, a single bolus intravenously of 16 mg / kg P5-NT, or 14 mg / kg P6-NT intravenously. A single bolus intravenous injec...

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Abstract

The present invention relates to short polypeptides (e.g., fewer than 19 amino acids in length) and longer polypeptides (e.g., 19 or more amino acids in length) having one or more D-amino acids as targeting moieties. These polypeptides, when conjugated to agents (e.g., therapeutic agents or transport vectors) are capable of transporting the agents across the BBB or into particular cell types. In particular, the short polypeptides can include one or more D- amino acids. These compounds are therefore particularly useful in the treatment of neurological diseases or diseases associated with particular cell types, organs, or tissues.

Description

technical field [0001] The present invention relates to short polypeptides which are (in part) useful as targeting moieties. The invention also relates to conjugates comprising a targeting moiety linked to a therapeutic agent or delivery vehicle and uses thereof. Background technique [0002] The brain is shielded from potentially toxic substances by two barrier systems: the blood-brain barrier (BBB) ​​and the blood-cerebrospinal fluid barrier (BCSFB). Since the BBB surface area is about 5000 times larger than that of BCSFB, the BBB is considered to be the major route for uptake of serum ligands. The brain endothelium (constituting the BBB) is a major obstacle to the use of potential drugs against many central nervous system (CNS) diseases. As a general rule, only small lipophilic molecules can pass through the BBB, ie from the blood of the circulatory system to the brain. Although many drugs with larger size or higher hydrophobicity have shown promising results in animal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06A61K38/16A61K47/48A61P35/00C07K14/00C07K19/00C07K7/08C07K14/575C07K14/605
CPCA61K38/2264A61K38/2278C07K2319/00A61K47/48246C07K14/8117A61K38/10A61K38/185A61K47/64A61P15/00A61P19/02A61P21/00A61P25/00A61P25/24A61P25/30A61P29/00A61P3/00A61P35/00A61P43/00A61P9/00A61P9/10A61P9/12Y02A50/30A61K47/6811
Inventor 让-保罗·卡斯泰恩米歇尔·德默勒克里斯蒂安·切卡里纳·蒂奥特劳伦斯·佩斯尔赫尔布
Owner ANGLACHEM INC
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