棕榈酸
脂肪酸
生物化学
白蛋白
生物
游离脂肪酸受体1
过氧化物酶体
牛血清白蛋白
结合
寡核苷酸
效力
骨骼肌
CD36
体外
基因
内分泌学
受体
数学分析
兴奋剂
数学
作者
Thazha P. Prakash,Adam E. Mullick,Richard G. Lee,Jinghua Yu,Shu-Hui Yeh,Audrey Low,Alfred E. Chappell,Michael E. Østergaard,Sue Murray,Hans Gaus,Eric E. Swayze,Punit P. Seth
摘要
Enhancing the functional uptake of antisense oligonucleotide (ASO) in the muscle will be beneficial for developing ASO therapeutics targeting genes expressed in the muscle. We hypothesized that improving albumin binding will facilitate traversal of ASO from the blood compartment to the interstitium of the muscle tissues to enhance ASO functional uptake. We synthesized structurally diverse saturated and unsaturated fatty acid conjugated ASOs with a range of hydrophobicity. The binding affinity of ASO fatty acid conjugates to plasma proteins improved with fatty acid chain length and highest binding affinity was observed with ASO conjugates containing fatty acid chain length from 16 to 22 carbons. The degree of unsaturation or conformation of double bond appears to have no influence on protein binding or activity of ASO fatty acid conjugates. Activity of fatty acid ASO conjugates correlated with the affinity to albumin and the tightest albumin binder exhibited the highest activity improvement in muscle. Palmitic acid conjugation increases ASO plasma Cmax and improved delivery of ASO to interstitial space of mouse muscle. Conjugation of palmitic acid improved potency of DMPK, Cav3, CD36 and Malat-1 ASOs (3- to 7-fold) in mouse muscle. Our approach provides a foundation for developing more effective therapeutic ASOs for muscle disorders.
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