Toth I
School of Pharmacy, University of London, U.K.
J Drug Target. 1994;2(3):217-39. doi: 10.3109/10611869408996805.
A novel infinity-amino acid based oligopeptide system has been designed, which combines structural features of lipids with those of amino acids and peptides. Because of their bifunctional nature, the fatty amino acids and peptides have the capacity to be chemically conjugated to drugs and peptides with a wide variety of functional groups. The linkage between drug and lipidic unit may either be biologically stable (ie. a new drug is formed) or exhibit biological or chemical instability (ie. the conjugate is a pro-drug). In either case, the resulting conjugates would be expected to possess a high degree of membrane-like character, which may be sufficient to facilitate their passage across membranes. The long alkyl side chains may also have the additional effect of protecting a labile parent drug from enzymatic attack. The lipidic system has been conjugated to a wide variety of different compounds, including (i) alkaloids (ii) beta-lactam antibiotics, (iii) anticancer compounds (iv) CNS drugs and (v) peptides. The biological examination of the conjugates showed that an increase in lipophilicity caused an increase in the in vitro cellular and in vivo oral uptake, as well as passage through the blood-brain-barrier, suggesting that conjugation to lipidic amino acids and peptides is a useful approach to improve the absorption of poorly-absorbed drugs. Lipidic conjugates of peptides (TRH, LHRH) resulted in higher enzymatic stability of the conjugates, proving that the long alkyl side chains also have the additional effect of protecting a labile parent drug or peptide in a biological environment. A novel Lipid-Core-Peptide (LCP) system has also been synthesised by incorporating lipidic amino acids to a lysine based polyamino acid system to enhance lipophilicity and membrane binding effects and the metabolic stability of the compound. The LCP system as a combined adjuvant-carrier-vaccine greatly increased the immunogenicity of synthetic peptides.
一种新型的基于无限氨基酸的寡肽系统已被设计出来，它结合了脂质与氨基酸及肽的结构特征。由于其双功能性质，脂肪族氨基酸和肽能够与具有多种官能团的药物和肽进行化学偶联。药物与脂质单元之间的连接既可以是生物稳定的（即形成一种新药物），也可以表现出生物或化学不稳定性（即偶联物是一种前药）。在任何一种情况下，所得到的偶联物都有望具有高度的膜样特性，这可能足以促进它们穿过膜。长烷基侧链还可能具有额外的作用，即保护不稳定的母体药物免受酶的攻击。脂质系统已与多种不同的化合物偶联，包括（i）生物碱（ii）β-内酰胺抗生素，（iii）抗癌化合物（iv）中枢神经系统药物和（v）肽。对偶联物的生物学检测表明，亲脂性的增加导致体外细胞摄取和体内口服吸收增加，以及穿过血脑屏障，这表明与脂质氨基酸和肽偶联是改善吸收不良药物吸收的一种有用方法。肽（TRH、LHRH）的脂质偶联物导致偶联物具有更高的酶稳定性，证明长烷基侧链在生物环境中也具有保护不稳定的母体药物或肽的额外作用。一种新型的脂质-核心-肽（LCP）系统也已通过将脂质氨基酸掺入基于赖氨酸的聚氨基酸系统中合成，以增强亲脂性和膜结合效应以及化合物的代谢稳定性。LCP系统作为一种联合佐剂-载体-疫苗极大地提高了合成肽的免疫原性。
