Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and

-The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i+4, i+7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead α-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an α-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.