Bioinspired Design of Lysolytic Triterpenoid–Peptide Conjugates that Kill African Trypanosomes

Humans have evolved a natural immunity against Trypanosoma brucei infections, which is executed by two serum (lipo)protein complexes known as trypanolytic factors (TLF). The active TLF ingredient is the primate‐specific apolipoprotein L1 (APOL1). The protein has a pore‐forming activity that kills parasites by lysosomal and mitochondrial membrane fenestration. Of the many trypanosome subspecies, only two are able to counteract the activity of APOL1; this illustrates its evolutionarily optimized design and trypanocidal potency. Herein, we ask whether a synthetic (syn) TLF can be synthesized by using the design principles of the natural TLF complexes but with different chemical building blocks. We demonstrate the stepwise development of triterpenoid–peptide conjugates, in which the triterpenoids act as a cell‐binding, uptake and lysosomal‐transport modules and the synthetic peptide GALA acts as a pH‐sensitive, pore‐forming lysolytic toxin. As designed, the conjugate kills infective‐stage African trypanosomes through lysosomal lysis thus demonstrating a proof‐of‐principle for the bioinspired, forward‐design of a synTLF.