Department of Chemistry, Lehigh University, Bethlehem, Pennsylvania 18015, United States.
Biochemistry. 2024 Apr 16;63(8):953-957. doi: 10.1021/acs.biochem.3c00721. Epub 2024 Mar 28.
A major challenge currently facing medicinal chemists is designing agents that can selectively destroy drug resistant fungi and bacteria that have begun to emerge. One factor that has been overlooked by virtually all drug discovery/development approaches is the supramolecular factor, in which aggregated forms of a drug candidate exhibit low selectivity in destroying targeted cells while the corresponding monomers exhibit high selectivity. This Perspective discusses how we were led to the supramolecular factor through fundamental studies with simple model systems, how we reasoned that the selectivity of monomers of the antifungal agent amphotericin B should be much greater than the selectivity of the corresponding aggregates, and how we confirmed this hypothesis using derivatives of amphotericin B. In a broader context, these findings provide a strong rationale for considering the supramolecular factor in the design of new drug candidates and the testing of virtually all of them.
目前，药物化学家面临的一个主要挑战是设计能够选择性地摧毁已经出现的耐药真菌和细菌的试剂。几乎所有的药物发现/开发方法都忽略了一个因素，即超分子因素，在这种因素中，候选药物的聚集形式在破坏靶细胞时表现出低选择性，而相应的单体则表现出高选择性。本文通过对简单模型系统的基础研究，讨论了我们如何得出超分子因素，以及我们如何推断抗真菌剂两性霉素 B 的单体的选择性应该远远大于相应聚集物的选择性，我们如何使用两性霉素 B 的衍生物来证实这一假设。从更广泛的角度来看，这些发现为在新候选药物的设计和几乎所有候选药物的测试中考虑超分子因素提供了强有力的理由。
