Cho Christy J, Kang Sangyoon, Pedebos Conrado, Khalid Syma, Brea Roberto J, Devaraj Neal K
Department of Chemistry and Biochemistry, University of California, San Diego La Jolla, CA 92093, USA.
Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom.
Angew Chem Int Ed Engl. 2025 May 12;64(20):e202421932. doi: 10.1002/anie.202421932. Epub 2025 Apr 7.
Membrane-forming phospholipids are generated in cells by enzymatic diacylation of non-amphiphilic polar head groups. Analogous non-enzymatic processes may have been relevant at the origin of life and could have practical utility in membrane synthesis. However, aqueous head group diacylation is challenging in the absence of enzymes. The use of charged peptides instead of canonical phospholipid head groups offers advantages with respect to ease of acylation and chemical diversity. Here we demonstrate that native chemical ligation (NCL) enables in situ synthesis of diacylated lipopeptides (D-ALPs), which spontaneously self-assemble into micron-sized vesicles resembling cellular membranes. Diacylation occurs between non-amphiphilic peptides possessing an N-terminal cysteine, and acyl thioesters. Peptide head groups endow unique membrane functions, which is demonstrated by incorporation of an arginine-glycine-aspartic acid (RGD) motif, resulting in vesicle targeting to αβ integrin-overexpressing cancer cells. The biocompatibility and functional group programmability of D-ALPs supports their broad utility as membrane mimetics.
形成膜的磷脂是通过非两亲性极性头部基团的酶促二酰化作用在细胞中产生的。类似的非酶促过程在生命起源时可能具有相关性，并且在膜合成中可能具有实际用途。然而，在没有酶的情况下，水性头部基团的二酰化具有挑战性。使用带电荷的肽代替典型的磷脂头部基团在酰化的容易程度和化学多样性方面具有优势。在这里，我们证明了天然化学连接（NCL）能够原位合成二酰化脂肽（D-ALP），其能自发地自组装成类似细胞膜的微米级囊泡。二酰化作用发生在具有N端半胱氨酸的非两亲性肽与酰基硫酯之间。肽头部基团赋予独特的膜功能，这通过掺入精氨酸-甘氨酸-天冬氨酸（RGD）基序得到证明，从而导致囊泡靶向过表达αβ整合素的癌细胞。D-ALP的生物相容性和官能团可编程性支持它们作为膜模拟物的广泛应用。
