拉福克萨尼德是一种萨利西拉尼利德杀虫剂,与人体血蛋白 transthyretin 相互作用
Takeshi Yokoyama1, Mineyuki Mizuguchi1, Yuko Nabeshima1
1Faculty of Pharmaceutical Sciences, University of Toyama, Japan.
The FEBS journal
|July 31, 2023
概括
拉福克萨尼德与跨甲状腺素 (TTR) 结合,抑制了粉样蛋白的形成. 然而,它的结合在人体血中减少,这表明潜在的甲状腺干扰和需要进一步研究作为抗粉症候选药物.
科学领域:
- 生物化学 生物化学
- 药理学 药理学是指药理学的学科.
- 结构生物学 结构生物学
背景情况:
- 晶氨酸 (TTR) 是甲状腺素 (T4) 的关键运输蛋白,并与ATTR氨基粉症有关.
- 与TTR相互作用的小分子可能会破坏甲状腺激素运输或稳定TTR,以防止粉样蛋白的形成.
研究的目的:
- 为了研究拉福克萨尼德的结合,一种杀虫剂药物,TTR.
- 评估rafoxanide作为TTR氨基代生成的抑制剂的潜力.
- 评估rafoxanide与其他甲状腺激素结合蛋白的相互作用及其在人体血中的行为.
主要方法:
- 内在光火试验以确定结合亲和力.
- 纤维化试验用于评估TTR氨基代的抑制.
- 蛋白质晶体学以阐明结合模式并指导优化.
主要成果:
- 拉福克萨尼德与TTR的T4结合部位结合,并抑制TTR的氨基代.
- 拉福克桑胺还与血清白蛋白和甲状腺激素受体β结合.
- 拉福克桑胺与TTR的结合在人体血中减少,这可能是由于与其他结合蛋白的竞争.
结论:
- 拉福克桑胺具有双重潜力,作为甲状腺破坏性化学物质和ATTR氨基粉症抑制剂的化合物.
- 需要进行进一步的结构研究,以优化rafoxanide的结合亲和力和选择性,以便治疗开发.
- 血蛋白相互作用对rafoxanide疗效的影响需要仔细考虑.
相关概念视频
01:29Drug Distribution: Plasma Protein Binding
5.7K
Drugs predominantly attach to plasma proteins, with only a small percentage remaining unbound. The unbound portion can be calculated as one minus the bound fraction. Acidic drugs form large, inactive complexes by reversibly binding to plasma albumin, which prevents them from diffusing across biological barriers. These drug-protein complexes act as reservoirs for the drugs. As the concentration of unbound drugs decreases, these complexes quickly dissociate to release the free drug, maintaining...
5.7K
01:09Hepatic Drug Clearance: Effect of Protein Binding
245
Hepatic clearance is influenced by protein binding based on the drug's extraction ratio. Drugs with high extraction ratios are considered flow-limited and remain unaffected by protein binding during hepatic clearance. On the other hand, drugs with low extraction ratios may be impacted by plasma protein binding, although the extent of this influence depends on the fraction of the drug bound.
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
245
01:11Renal Failure: Dose Adjustments
122
In patients with renal impairment, drugs undergo significant changes in their pharmacokinetics, which require dosage adjustments to ensure safe and effective therapy.
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...
122
01:28Renal Drug Excretion: Tubular Secretion
224
Active tubular secretion is a robust, energy-demanding process that utilizes carrier systems to transport drugs into renal tubules. The active renal secretion systems include the organic anion transporter (OAT) for weak acids and the organic cation transporter (OCT) for weak bases. Structurally similar drugs can compete for the same transporter, potentially leading to drug accumulation and toxicity. However, this principle can be exploited therapeutically. One example is probenecid (Probalan),...
224
01:31Factors Affecting Renal Clearance: Drug's Physicochemical Properties and Plasma Levels
260
Renal clearance of a drug is influenced by various factors, including its physicochemical properties and plasma levels. These factors play a significant role in determining how efficiently the kidneys eliminate a drug.
One important factor is the drug's molecular size. The kidneys readily excrete smaller molecules below 300 Daltons (Da). On the other hand, molecules weighing between 300 and 500 Da are excreted through both urine and bile. Larger molecules above 500 Da tend to be excreted...
One important factor is the drug's molecular size. The kidneys readily excrete smaller molecules below 300 Daltons (Da). On the other hand, molecules weighing between 300 and 500 Da are excreted through both urine and bile. Larger molecules above 500 Da tend to be excreted...
260
01:09Factors Affecting Renal Clearance: Drug Distribution and Drug Interactions
164
Renal clearance plays a pivotal role in drug elimination from the body and can be influenced by drug distribution and interactions. Understanding these factors is crucial in pharmacology as they impact the effectiveness and duration of drug therapy.
One important factor is the relationship between renal clearance and the apparent volume of distribution. Renal clearance tends to be inversely proportional to the apparent volume of distribution. Drugs with an extensive distribution volume or those...
One important factor is the relationship between renal clearance and the apparent volume of distribution. Renal clearance tends to be inversely proportional to the apparent volume of distribution. Drugs with an extensive distribution volume or those...
164