A chemically programmed antibody is a long-lasting and potent inhibitor of influenza neuraminidase.
A chemically programmed antibody is a long-lasting and potent inhibitor of influenza neuraminidase.
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DOI：
10.1002/cbic.201200439
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发表时间：
2012-10-15
期刊：
影响因子：
3.2
通讯作者：
Barbas, Carlos F., III
中科院分区：
文献类型：
--
作者：
Hayakawa, Masahiko;Toda, Narihiro;Carrillo, Nancy;Thornburg, Natalie J.;Crowe, James E., Jr.;Barbas, Carlos F., III
全球化使得反复发生的流感大流行成为可预见的未来可能出现的医疗保健问题。[1]虽然疫苗接种在预防流感流行和大流行中发挥着主要作用，但疫苗必须在流感季节之前设计和生产，不能根据病毒突变按需供应。 [2]因此，在流行病管理中，有效的抗流感药物与疫苗接种一样重要。 [3]目前，神经氨酸酶抑制剂扎那米韦(1)[4]和奥司他韦(2)[5]是治疗感染患者的主要药物（图1）。由于它们从体内快速排泄，因此每种药物必须每天给药两次。因此，长效、强效的抗流感药物是治疗和预防流感感染的极具吸引力的替代品。[6]我们开发了一种制备化学编程抗体的策略，这些抗体具有抗体的长半衰期和效应功能以及缀合小分子药物、肽或寡核苷酸的治疗活性（图2）。[7]与抗体缀合的试剂首先用 β-内酰胺进行功能化，然后选择性地与醛缩酶单克隆抗体 (mAb) 38C2 催化活性关键的低 pKa 赖氨酸残基反应，形成酰胺键。作为旨在开发新型抗流感药物和化学编程疫苗策略的项目的一部分，我们用化学编程了一种带有针对神经氨酸酶的小分子酶抑制剂的抗体。我们的目标是创造一种新型有效的神经氨酸酶抑制剂，该抑制剂可维持长期的全身暴露，并有可能通过抗体相关的效应器功能和效价增强活性。迄今为止，化学编程抗体尚未利用酶抑制剂作为特异性编程剂。成功招募酶抑制剂作为编程剂将使多种酶抑制剂成为针对免疫反应的有效新治疗工具。
Globalization makes reoccurring influenza pandemics a probable health care concern for the foreseeable future.[1] Although vaccination plays a primary role in the prevention of influenza epidemics and pandemics, vaccines must be designed and produced in advance of the influenza season and cannot be supplied on-demand in response to virus mutation.[2] Thus, efficient anti-influenza drugs are as important as vaccination in epidemic management.[3] Currently, the neuraminidase inhibitors zanamivir (1)[4] and oseltamivir (2)[5] are the mainstay drugs for treatment of infected patients (Figure 1). Each must be administered twice-daily due to their rapid excretion from the body. Therefore, long-lasting and potent anti-influenza drugs are highly attractive alternatives for treatment of influenza infection as well as for prophylaxis.[6]We have developed a strategy to prepare chemically programmed antibodies that have the long half-life and effector function of the antibody and therapeutic activity of the conjugated small-molecule drug, peptide, or oligonucleotide (Figure 2).[7] The agent to be conjugated to the antibody is first functionalized with a β-lactam and then is selectively reacted with the low pKa lysine residues key to the catalytic activity of aldolase monoclonal antibody (mAb) 38C2 to form an amide bond. As part of a project aimed at developing novel anti-influenza agents and chemically programmed vaccine strategies, we have chemically programmed an antibody with a small molecule enzyme inhibitor that targets neuraminidase. Our goal was to create a novel potent neuraminidase inhibitor that maintains long-term systemic exposure with the potential for enhanced activity through antibody associated effector function and valency. To date, chemically programmed antibodies have not utilized enzyme inhibitors as specificity programming agents. Successful recruitment of enzyme inhibitors as programming agents would make a wide-range of enzyme inhibitors effective new therapeutic tools for targeting an immune response.
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