Design of non‐peptidic helix/sheet topomimetics: applications to bacterial endotoxin neutralization and inhibition of angiogenesis and tumor growth in mice

Abstract

We report here the design of non-peptidic calixarene-based compounds that display chemical substituents to approximate the molecular dimensions and surface topology of amphipathic α-helix and β-sheet peptides. From a small library of these calixarene-based topomimetics, we demonstrate that some of them mimic the biological activities of model peptides SC4 and anginex by neutralizing bacterial endotoxin lipopolysaccharide (LPS), and by inhibiting angiogenesis and tumor growth in mice. Several calixarene-based topomimetics neutralize LPS in the 10-8 to 10-9 M range in vitro, and a few of these are protective in vivo against LPS challenge to mice. Other compounds within the library are potent angiogenesis inhibitors, as determined by endothelial cell proliferation and migration assays in vitro, and by the chick embryo chorioallantoic membrane (CAM) assay in vivo. In human ovarian carcinoma and murine melanoma tumor models in mice, these compounds are highly effective at inhibiting tumor angiogenesis and tumor growth. Our results demonstrate the feasibility of designing non-peptidic helix/sheet topomimetics as novel therapeutic agents. This work was supported by a research grant to KHM from the National Institute of Allergy and Infectious Diseases through the Greater Lakes Research Center of Excellence (GLRCE) for Biodefense and Emerging Infectious Diseases (U54 AI057153).