Withers-Martinez Chrislaine, Lidumniece Elina, Hackett Fiona, Collins Christine R, Taha Zahie, Blackman Michael J, Jirgensons Aigars
Malaria Biochemistry Laboratory, The Francis Crick Institute, London NW1 1AT, U.K.
Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia.
J Med Chem. 2024 Aug 8;67(15):13033-13055. doi: 10.1021/acs.jmedchem.4c01005. Epub 2024 Jul 25.
subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P amino acid side chains as well as -capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P position, replacing the methyl group with a carboxyethyl substituent led to boralactone PfSUB1 inhibitors with remarkably improved selectivity over H20S. Combining lipophilic end-capping groups with the boralactone reduced the selectivity over H20S. However, compound still showed >60-fold selectivity versus H20S and low nanomolar PfSUB1 inhibitory potency. Importantly, this compound inhibited the growth of a genetically modified line expressing reduced levels of PfSUB1 13-fold more efficiently compared to a wild-type parasite line.
枯草杆菌蛋白酶样丝氨酸蛋白酶1（PfSUB1）对于疟原虫侵袭性裂殖子形式的逸出至关重要，这使得PfSUB1成为一个有吸引力的抗疟靶点。在此，我们报告旨在改善肽硼酸PfSUB1抑制剂类药物特性的研究，包括提高亲脂性以及对人蛋白酶体（H20S）的选择性。构效关系研究表明，亲脂性的P氨基酸侧链以及封端基团在保留PfSUB1抑制活性方面具有良好的耐受性。在P位，用羧乙基取代基取代甲基可得到对H20S选择性显著提高的硼内酯PfSUB1抑制剂。将亲脂性封端基团与硼内酯结合会降低对H20S的选择性。然而，化合物 对H20S的选择性仍>60倍，且对PfSUB1具有低纳摩尔抑制活性。重要的是，与野生型寄生虫株相比，该化合物抑制表达水平降低的PfSUB1的基因改造株生长的效率高出13倍。
