Kudirka Romas, Barfield Robyn M, McFarland Jesse, Albers Aaron E, de Hart Gregory W, Drake Penelope M, Holder Patrick G, Banas Stefanie, Jones Lesley C, Garofalo Albert W, Rabuka David
Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
Chem Biol. 2015 Feb 19;22(2):293-8. doi: 10.1016/j.chembiol.2014.11.019. Epub 2015 Jan 22.
There is a need for facile chemistries that allow for chemo- and regioselectivity in bioconjugation reactions. To address this need, we are pioneering site-specific bioconjugation methods that use formylglycine as a bioorthogonal handle on a protein surface. Here we introduce aldehyde-specific bioconjugation chemistry, the trapped-Knoevenagel ligation. The speed and stability of the trapped-Knoevenagel ligation further advances the repertoire of aldehyde-based bioconjugations and expands the toolbox for site-specific protein modifications. The trapped-Knoevenagel ligation reaction can be run at near neutral pH in the absence of catalysts to produce conjugates that are stable under physiological conditions. Using this new ligation, we generated an antibody-drug conjugate that demonstrates excellent efficacy in vitro and in vivo.
需要有简便的化学方法，以实现生物共轭反应中的化学选择性和区域选择性。为满足这一需求，我们正在开创位点特异性生物共轭方法，该方法利用甲酰甘氨酸作为蛋白质表面的生物正交手柄。在此，我们介绍醛特异性生物共轭化学，即捕获的克诺文纳格尔连接反应。捕获的克诺文纳格尔连接反应的速度和稳定性进一步拓展了基于醛的生物共轭反应库，并扩大了用于位点特异性蛋白质修饰的工具箱。捕获的克诺文纳格尔连接反应可以在接近中性的pH值下、无催化剂的情况下进行，以生成在生理条件下稳定的共轭物。利用这种新的连接反应，我们制备了一种抗体-药物共轭物，该共轭物在体外和体内均表现出优异的疗效。
