调整固醇提取动力学产生节约的聚抗真菌
Arun Maji1,2,3,4, Corinne P Soutar2,3,5, Jiabao Zhang2,3
1Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nature
|November 8, 2023
概括
研究人员开发了新的抗真菌药物,发现向的是真菌的ergosterol提取物,而不是细胞膜,导致像AM-2-19这样的强效和节约的多抗真菌药物.
科学领域:
- 医学化学
- 菌群学
- 药理学
背景情况:
- 传统的聚抗真菌开发是基于有缺陷的膜透模型.
- 氨基酸B是一种重要的抗真菌药物,通过从细胞膜中提取固醇,引起毒性.
- 菌埃尔戈斯特的提取,而不是膜破坏,是安福特B抗真菌作用的主要机制.
研究的目的:
- 开发强效的多抗真菌剂,
- 了解和减轻与安福特B相关的毒性
- 通过调整分子相互作用动态来合理设计新型抗真菌药物.
主要方法:
- 研究了安波特B的抗真菌和毒性作用的机制.
- 采用高分辨率的安福特B-复合物的结构分析.
- 设计和合成了包括AM-2-19在内的安福特B的结构衍生物,并评估了它们的疗效和毒性.
主要成果:
- 确定胆固醇提取是安福特B的毒性的驱动因素.
- 开发了一种节衍生物 (AM-2-19),可以选择性地和快速地提取真菌厄戈斯特醇,而不会结合胆固醇.
- 在入侵性真菌感染的临床前模型中,AM- 2-19表现出强烈的抗真菌活性,耐药性回避和有效性.
结论:
- 基于分子相互作用动态的理性设计可以产生更好的抗真菌疗法.
- 向埃尔戈斯特提取提供了一种有前途的策略,用于开发强效,安全和抗性避菌药物.
- 新型聚烯AM-2-19在治疗危及生命的真菌感染方面取得了重大进展.
相关概念视频
Drug Elimination by Renal Route: Tubular Secretion
2.4K
Once the process of glomerular filtration is completed, blood carrying unfiltered drug molecules traverses through efferent arterioles and makes its way into the peritubular capillaries in the proximal tubule. A variety of carriers play a pivotal role in actively secreting drugs from these peritubular capillaries into the tubular fluid. The organic anion transporter transfers acidic drugs, against an electrochemical gradient, from the peritubular capillaries into the renal tubule cells and...
2.4K
Factors Affecting Renal Clearance: Drug's Physicochemical Properties and Plasma Levels
241
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...
241
Renal Drug Excretion: Tubular Secretion
195
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),...
195
Renal Failure: Dose Adjustments
96
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...
96
Kinetics of Drug Elimination
3.4K
Eliminating drugs from the body is a vital process that occurs through excretion or metabolism. Understanding the kinetics of drug elimination is crucial for drug development, dosage determination, and optimizing patient outcomes.
Drug clearance depends on the rate of drug elimination and its plasma concentration. Another important parameter is the half-life of a drug, which is the time required for its concentration to decrease by half. In most cases, drug clearance follows first-order...
Drug clearance depends on the rate of drug elimination and its plasma concentration. Another important parameter is the half-life of a drug, which is the time required for its concentration to decrease by half. In most cases, drug clearance follows first-order...
3.4K
Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
209
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
209


