Gare Caitlin L, Palombi Isabella R, White Andrew M, Chavchich Marina, Edstein Michael D, Lock Aaron, Avery Vicky M, Craik David J, McMorran Brendan J, Lawrence Nicole, Malins Lara R
Research School of Chemistry, The Australian National University, Canberra, ACT, 2601, Australia.
Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The Australian National University, Canberra, ACT, 2601, Australia.
ChemMedChem. 2025 Jan 14;20(2):e202400637. doi: 10.1002/cmdc.202400637. Epub 2024 Nov 12.
The devastating impact of malaria includes significant mortality and illness worldwide. Increasing resistance of the causative parasite, Plasmodium, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide-drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell-penetrating peptides. This approach aims to enhance selective uptake into Plasmodium-infected red blood cells and impart additional cytotoxic actions on the intraerythrocytic parasite, thereby enabling targeted drug delivery and dual modes of action. We describe the development of PDCs featuring four compounds with antimalarial activity-primaquine, artesunate, tafenoquine and methotrexate-conjugated to three cell-penetrating peptide scaffolds with varied antiplasmodial activity, including active and inactive analogues of platelet factor 4 derived internalization peptide (PDIP), and a cyclic polyarginine peptide. Development of this diverse set of PDCs featured distinct and adaptable conjugation strategies, to produce conjugates with in vitro antiplasmodial activities ranging from low nanomolar to low micromolar potencies according to the drug cargo and bioactivity of the partner peptide. Overall, this study establishes a strategic and methodological framework for the further development of dual mode of action peptide-drug antimalarial therapeutics.
疟疾的破坏性影响包括在全球范围内造成重大的死亡和疾病。致病寄生虫疟原虫对现有抗疟药物的耐药性不断增加，这凸显了在治疗研发流程中需要有更多具有不同作用模式的化合物。在此，我们展示了肽-药物偶联物（PDC）作为一类有吸引力的化合物，其中治疗性或先导抗疟药物与细胞穿透肽进行化学偶联。这种方法旨在增强对疟原虫感染红细胞的选择性摄取，并对红细胞内的寄生虫产生额外的细胞毒性作用，从而实现靶向药物递送和双重作用模式。我们描述了具有四种抗疟活性化合物（伯氨喹、青蒿琥酯、tafenoquine和甲氨蝶呤）与三种具有不同抗疟活性的细胞穿透肽支架偶联的PDC的开发，这些支架包括血小板因子4衍生内化肽（PDIP）的活性和非活性类似物，以及一种环状聚精氨酸肽。开发这一系列多样的PDC采用了独特且可调整的偶联策略，以根据药物载荷和伙伴肽的生物活性产生体外抗疟活性范围从低纳摩尔到低微摩尔效力的偶联物。总体而言，本研究为双作用模式肽-药物抗疟疗法的进一步开发建立了一个战略和方法框架。
