A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.
A TfR-Binding Cystine-Dense Peptide Promotes Blood-Brain Barrier Penetration of Bioactive Molecules.
复制标题
DOI：
10.1016/j.jmb.2020.04.002
复制
发表时间：
2020-06-26
影响因子：
5.6
通讯作者：
Olson JM
中科院分区：
文献类型：
--
作者：
Crook ZR;Girard E;Sevilla GP;Merrill M;Friend D;Rupert PB;Pakiam F;Nguyen E;Yin C;Ruff RO;Hopping G;Strand AD;Finton KAK;Coxon M;Mhyre AJ;Strong RK;Olson JM
血脑屏障（BBB）对大多数常规药物的不可渗透性阻碍了中枢神经系统（CNS）疾病的治疗。针对脑癌、神经退行性疾病或与年龄相关的炎症过程等疾病的干预措施需要多种中枢神经系统药物递送方法。半胱氨酸密集肽（CDPs）作为药物或药物递送载体近来受到关注。它们在整个系统发育树中都有发现，通常具有类似药物的作用，其大小、稳定性和蛋白质相互作用能力使CDPs成为一种有吸引力的中等大小生物支架，可补充传统的基于抗体的药物。在此，我们描述了一种与转铁蛋白受体（TfR）结合的CDP的鉴定、成熟、特性和应用，TfR是铁伴侣转铁蛋白的一种天然受体和血脑屏障转运蛋白。我们开发了具有不同结合亲和力（解离常数KD低至216皮摩尔）的变体，将其与受体共结晶，并确认了小鼠的交叉反应性。它在小鼠中枢神经系统中的积累量约为血液水平的25%（中枢神经系统血液含量仅约为1 - 6%），并能递送神经降压素（一种原本无法穿透血脑屏障的神经肽），其递送量能够调节小鼠大脑中的环磷腺苷效应元件结合蛋白（CREB）信号。我们的工作强调了CDPs作为一个多样的、易于筛选的支架家族在现代药物发现策略中的实用性，通过发现一种可用于进一步优化和临床前开发的中枢神经系统候选药物递送载体得以证明。
The impenetrability of the blood-brain barrier (BBB) to most conventional drugs impedes the treatment of central nervous system (CNS) disorders. Interventions for diseases like brain cancer, neurodegeneration, or age-associated inflammatory processes require varied approaches to CNS drug delivery. Of recent interest as drugs or drug-delivery vehicles are cystine-dense peptides (CDPs). Found throughout the phylogenetic tree, often in drug-like roles, their size, stability, and protein interaction capabilities make CDPs an attractive mid-size biologic scaffold to complement conventional antibody-based drugs. Here, we describe the identification, maturation, characterization, and utilization of a CDP that binds to the transferrin receptor (TfR), a native receptor and BBB transporter for the iron chaperone transferrin. We developed variants with varying binding affinities (KD as low as 216 pM), co-crystallized it with the receptor, and confirmed murine cross-reactivity. It accumulates in the mouse CNS at ~25% of blood levels (CNS blood content is only ~1–6%), and delivers neurotensin, an otherwise non-BBB-penetrant neuropeptide, at levels capable of modulating CREB signaling in the mouse brain. Our work highlights the utility of CDPs as a diverse, easy-to-screen scaffold family worthy of inclusion in modern drug discovery strategies, demonstrated by the discovery of a candidate CNS drug delivery vehicle ready for further optimization and preclinical development.
登录
查看更多内容
影响因子：
3
作者：
Daniels, Tracy R.;Bernabeu, Ezequiel;Rodriguez, Jose A.;Patel, Shabnum;Kozman, Maggie;Chiappetta, Diego A.;Holler, Eggehard;Ljubimova, Julia Y.;Helguera, Gustavo;Penichet, Manuel L.
通讯作者：
Penichet, Manuel L.
影响因子：
16.6
作者：
Crook ZR;Sevilla GP;Friend D;Brusniak MY;Bandaranayake AD;Clarke M;Gewe M;Mhyre AJ;Baker D;Strong RK;Bradley P;Olson JM
通讯作者：
Olson JM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.2
作者：
Herzig V;King GF
通讯作者：
King GF
影响因子：
14.9
作者：
UniProt Consortium
通讯作者：
UniProt Consortium