Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation.
Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation.
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DOI：
10.1073/pnas.2012266117
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发表时间：
2020-12-08
影响因子：
11.1
通讯作者：
Suga H
中科院分区：
文献类型：
--
作者：
Bashiruddin NK;Hayashi M;Nagano M;Wu Y;Matsunaga Y;Takagi J;Nakashima T;Suga H
骨质疏松症影响全球超过7500万人，这一数字随着全球中位年龄的增加而增加。因此，开发具有新的作用机制的治疗剂是非常重要的。抑制丛蛋白B1-脑信号蛋白4D对成骨细胞的相互作用已被证明是开发骨合成代谢模式的潜在靶点。在这里，使用一种新的环肽亲和力成熟方法，我们能够开发出紧密结合人类和小鼠丛蛋白B1并抑制其与脑信号蛋白4D相互作用的环肽。该肽的化学二聚化导致活性进一步增加，并在骨质疏松症小鼠模型中证明了骨丢失的完全拯救。骨质疏松症是由骨吸收和骨形成之间的不平衡引起的。骨质疏松症的治疗药物可分为抑制骨吸收的抗吸收药和增加骨形成的合成代谢药。目前，唯一的合成代谢治疗选择是甲状旁腺激素模拟物或抗硬化素单克隆抗体。随着目前全球骨质疏松症风险人口的增加，开发通过替代机制引起合成代谢活性的治疗方法势在必行。阻断丛蛋白B1和脑信号蛋白4D对成骨细胞的相互作用已被证明是增加骨形成的一种有前途的机制。在这里，我们报告了一种新的RaPID（随机非标准肽集成发现）系统为基础的亲和力成熟的方法，产生的肽PB 1 m6 A9，具有高亲和力结合到人类和小鼠丛蛋白B1的环肽的发现。化学二聚肽PB 1d 6A 9在小鼠原代成骨细胞培养中显示出对丛蛋白B1信号传导的强效抑制，即使与非Semaphorin 4D处理的对照相比，也能显著增强骨形成。当每周一次向卵巢切除小鼠静脉内给予脂化的PB 1d 6A 9（PB 1d 6A 9-β-D）时，也在体内观察到这种高合成代谢活性，导致骨丢失的完全挽救。这种肽的强效成骨特性显示出很大的希望，作为目前骨疾病如骨质疏松症的合成代谢治疗选择的补充。
Osteoporosis affects over 75 million people globally, and this number is increasing with global median age. Therefore, the development of therapeutics with novel mechanisms of action is of high importance. Inhibition of the PlexinB1-Semaphorin4D interaction on osteoblasts has been shown to be a potential target for developing osteoanabolic modalities. Here, using a novel affinity maturation approach for cyclic peptides, we were able to develop cyclic peptide that tightly binds human and mouse PlexinB1 and inhibits its interaction with Semaphorin4D. Chemical dimerization of this peptide resulted in further increases in activity and demonstrated complete rescue of bone loss in an osteoporosis mouse model. Osteoporosis is caused by a disequilibrium between bone resorption and bone formation. Therapeutics for osteoporosis can be divided into antiresorptives that suppress bone resorption and anabolics which increase bone formation. Currently, the only anabolic treatment options are parathyroid hormone mimetics or an anti-sclerostin monoclonal antibody. With the current global increases in demographics at risk for osteoporosis, development of therapeutics that elicit anabolic activity through alternative mechanisms is imperative. Blockade of the PlexinB1 and Semaphorin4D interaction on osteoblasts has been shown to be a promising mechanism to increase bone formation. Here we report the discovery of cyclic peptides by a novel RaPID (Random nonstandard Peptides Integrated Discovery) system-based affinity maturation methodology that generated the peptide PB1m6A9 which binds with high affinity to both human and mouse PlexinB1. The chemically dimerized peptide, PB1d6A9, showed potent inhibition of PlexinB1 signaling in mouse primary osteoblast cultures, resulting in significant enhancement of bone formation even compared to non-Semaphorin4D–treated controls. This high anabolic activity was also observed in vivo when the lipidated PB1d6A9 (PB1d6A9-Pal) was intravenously administered once weekly to ovariectomized mice, leading to complete rescue of bone loss. The potent osteogenic properties of this peptide shows great promise as an addition to the current anabolic treatment options for bone diseases such as osteoporosis.
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影响因子：
16.6
作者：
Ito, Kenichiro;Sakai, Katsuya;Suzuki, Yoshinori;Ozawa, Naoya;Hatta, Tomohisa;Natsume, Tohru;Matsumoto, Kunio;Suga, Hiroaki
通讯作者：
Suga, Hiroaki
影响因子：
16.6
作者：
Kawamura A;Münzel M;Kojima T;Yapp C;Bhushan B;Goto Y;Tumber A;Katoh T;King ON;Passioura T;Walport LJ;Hatch SB;Madden S;Müller S;Brennan PE;Chowdhury R;Hopkinson RJ;Suga H;Schofield CJ
通讯作者：
Schofield CJ
DOI：
10.1093/gerona/glt046
发表时间：
2013-10-01
影响因子：
5.1
作者：
Jilka, Robert L.
通讯作者：
Jilka, Robert L.
影响因子：
21.8
作者：
Nawatha, Mickal;Rogers, Joseph M.;Brik, Ashraf
通讯作者：
Brik, Ashraf
影响因子：
18.3
作者：
Zondlo, Neal J.
通讯作者：
Zondlo, Neal J.