一个不可逆转的STING对手LB244的开发
Leonard Barasa1,2, Sauradip Chaudhuri1,2, Jeffrey Y Zhou3
1Program in Chemical Biology, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, Massachusetts 01605, United States.
Journal of the American Chemical Society
|September 11, 2023
概括
研究人员开发了一种强大的STING抑制剂LB244,用于治疗ALS和狼等炎症性疾病. 这种化合物建立在BB-Cl-amidine的基础上,在体内表现出类似的疗效.
科学领域:
- 免疫学
- 生物化学
- 药理学
背景情况:
- 在检测细胞质dDNA和启动炎症反应方面,cGMP-AMP合成酶 (cGAS) - 干扰基因刺激器 (STING) 途径至关重要.
- 失调的STING信号与自身免疫和自身炎症性疾病有关,包括ALS,狼,艾卡迪-古提耶氏综合征 (AGS) 和在婴儿期出现的STING相关血管病变 (SAVI).
研究的目的:
- 与之前识别的化合物相比,开发新的STING抑制剂,其强度和蛋白质组范围的选择性得到改善.
- 在临床前模型中评估这些新抑制剂的治疗潜力.
主要方法:
- 基于BB-Cl-amidine的STING抑制剂的设计和合成
- 在体外生化测试以确定功效和全蛋白质选择性.
- 评估治疗效果的体内疗效研究.
主要成果:
- LB244在抑制STING信号方面表现出纳米分子效力.
- LB244具有显著增强的全蛋白质选择性.
- 在体内,LB244的疗效与BB-Cl-amidine相当.
结论:
- LB244是一种强效和选择性的STING抑制剂.
- 已发现的化学支架有望开发用于STING依赖性炎症的治疗方法.
- 进一步开发LB244和相关化合物可能会导致异常STING激活导致的疾病的新疗法.
相关概念视频
Local Anesthetics: Chemistry and Structure-Activity Relationship
4.4K
Local anesthetics (LAs) are drugs that induce a temporary loss of sensation in a limited body area, preventing pain. Cocaine was the first local anesthetic discovered in the late 19th century. Cocaine is a benzoic acid ester obtained from the leaves of coca shrubs and was often used for its psychotropic effects. Cocaine was first isolated in 1860 by Albert Niemann. Sigmund Freud studied the physiological actions of cocaine. Carl Koller later introduced it into clinical practice in 1884 as a...
4.4K
Local Anesthetics: Mechanism of Action
2.3K
Local anesthetics (LAs) block sensory and motor impulses by inhibiting the sodium channels on the nerve cell membranes. This induces temporary loss of sensation, relieving pain in a specific body area.
Local anesthetics are amphiphilic molecules consisting of a hydrophobic aromatic part linked to a hydrophilic group by an ester or amide linkage. They are weak bases and are usually available as salts, which increases their solubility and stability. Once administered, LAs exist in the body either...
Local anesthetics are amphiphilic molecules consisting of a hydrophobic aromatic part linked to a hydrophilic group by an ester or amide linkage. They are weak bases and are usually available as salts, which increases their solubility and stability. Once administered, LAs exist in the body either...
2.3K
Local Anesthetics: Clinical Application as Intravenous Regional Anesthesia
457
Intravenous regional anesthesia or the Bier block technique is used to anesthetize a specific limb or extremity. It uses exsanguinated or blood-drained vessels to transport local anesthetics or LAs to the peripheral nerve trunks. Lidocaine without vasoconstrictors like epinephrine is most commonly used for this technique. Other drugs used are prilocaine, ropivacaine, and chloroprocaine. Bupivacaine is not recommended for this technique due to its high cardiac toxicity.
One of the advantages of...
One of the advantages of...
457
Local Anesthetics: Common Agents and Their Applications
479
Local anesthetics (LAs) are commonly used for various applications in medical and dental procedures. Some of the common agents used are cocaine, lidocaine, and bupivacaine.
Cocaine is an ester of benzoic acid and methylecgogine. It is used to anesthetize and vasoconstrict locally. Currently, it is used primarily for topical applications. It is beneficial for surgeries on the upper respiratory tract, providing anesthesia and shrinking the mucosa. Cocaine in the form of cocaine hydrochloride is...
Cocaine is an ester of benzoic acid and methylecgogine. It is used to anesthetize and vasoconstrict locally. Currently, it is used primarily for topical applications. It is beneficial for surgeries on the upper respiratory tract, providing anesthesia and shrinking the mucosa. Cocaine in the form of cocaine hydrochloride is...
479
Local Anesthetics: Differential Sensitivity of Nerve Fibers
864
Local anesthetics (LAs) block the sodium channels of nerve trunks, sensory nerve endings, and neuromuscular junctions. Although LAs can block all kinds of nerves, the sensitivity of nerve fibers differs according to nerve types and structures. LAs are known to block myelinated fibers faster than unmyelinated ones. Also, they block pain or sensory neurons at low concentrations without affecting the motor neurons involved in muscle contractions. This helps relieve labor pain without affecting the...
864
Depolarizing Blockers: Pharmocokinetics
352
Depolarizing blockers are administered through intravenous injection. Succinylcholine is the most common choice of depolarizing blockers in emergency clinical practices. Although they have a rapid onset, they readily diffuse away from the motor end plate into the extracellular fluid. They are metabolized by enzymes such as liver butyrylcholinesterase and plasma pseudocholinesterases. This produces a short duration of action, typically 5-10 minutes long, unlike nondepolarizing blockers, which...
352


