Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the drug is masked and is recovered within the human body upon bioconversion of the prodrug, a process that is typically mediated by enzymes. This concept is highly successful and a significant fraction of marketed therapeutic formulations is based on prodrugs. An advanced subset of prodrugs can be engineered such as to achieve site-specific bioconversion of the prodrug – to comprise the highly advantageous “enzyme prodrug therapy”, EPT. Design of prodrugs for EPT is similar to the prodrugs in general medicinal use in that the pharmacological activity of the drug is masked, but differs significantly in that site-specific bioconversion is a prime consideration, and the enzymes typically used for EPT are non-mammalian and/or with low systemic abundance in the human body. This review focuses on the design of prodrugs for EPT in terms of the choice of an enzyme and the corresponding prodrug for bioconversion. We also discuss the recent success of “self immolative linkers” which significantly empower and diversify the prodrug design, and present methodologies for the design of prodrugs with extended blood residence time. The review aims to be of specific interest for medicinal chemists, biomedical engineers, and pharmaceutical scientists.

前药是治疗剂的狡猾衍生物，旨在改善药物的药代动力学特性。在前药中，该药的药理活性被掩盖并在前药生物转化后在人体内恢复，该过程通常由酶介导。该概念非常成功，并且市售的治疗制剂中有很大一部分是基于前药的。可以设计先进的前药子集，以实现前药的特定位点生物转化-包括高度有利的“酶前药疗法” EPT。用于EPT的前药设计与一般医学用途中的前药相似，因为该药的药理活性被掩盖，但是在主要针对位点的生物转化方面存在显着差异，并且通常用于EPT的酶是非哺乳动物的和/或在人体中具有低的系统丰度。本文就酶的选择和用于生物转化的相应前药，着重于EPT前药的设计。我们还讨论了“自焚连接体”的最新成功，该连接体显着增强了前药设计的能力并使其多样化，并介绍了具有较长血液滞留时间的前药设计方法。该审查旨在使药物化学家，生物医学工程师和药物科学家特别感兴趣。我们还讨论了“自焚连接体”的最新成功，该连接体显着增强了前药设计的能力并使其多样化，并介绍了具有较长血液滞留时间的前药设计方法。该审查旨在使药物化学家，生物医学工程师和药物科学家特别感兴趣。我们还讨论了“自焚连接体”的最新成功，该连接体显着增强了前药设计的能力并使其多样化，并介绍了具有较长血液滞留时间的前药设计方法。该审查旨在使药物化学家，生物医学工程师和药物科学家特别感兴趣。