The goal of this project is the development of a novel class of bi-functional antimalaria therapeutics based on the specific inhibition of hemoglobin degrading proteases of the parasite Plasmodium falciparum. The chemistry technology platform at ENANTA Pharmaceuticals is unique in the extensive use of stereochemistry in a focused library format. The strategy is to systematically replace amide bonds in suitable peptide leads that bind to or inhibit the targeted proteases by modules bearing several chiral centers. The assembly of these new compounds is modular using N- terminal and C-terminal monomers with distinct stereochemistries. The combination of all monomers leads to libraries of compounds with identical chemical composition, but different and distinct shapes and physical properties. Also, unlike active compounds found in random screening of chemical databases our structures exhibit a 'natural product'- like character. Consequently, we believe that our compound libraries are very unique and pharmacologically less risky. The general approach as well as the structures of the proposed compounds are novel and would, if successfully developed, target two of the main concerns in the fight against malaria. Firstly, the targets of the compounds are different from those of current anti malaria therapeutics. Secondly, the bifunctional activity of the compounds against two different classes of hemoglobin-degrading proteases, the aspartic acid proteases plasmepsin I and II on one hand, and the papain family cysteine protease falcipain on the other will result in a synergistic effect possibly allowing for lower dosage. Lower dosage in turn will be more economic and possibly less problematic pharmacologically in terms of toxicity and general side effects. Furthermore, such an approach will represent an important new weapon against the increasing occurrence of resistance.
