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Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/ acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption. [ABSTRACT FROM AUTHOR]

By virtual screening, compound 1was foundto be activeagainst NS2B-NS3 protease (IC50= 13.12 ± 1.03 μM).Fourteen derivatives (22) of compound 1weresynthesized, leading to the discovery of four new inhibitors withbiological activity. In order to expand the chemical diversity ofthe inhibitors, small-molecule-based scaffold hopping was performedon the basis of the common scaffold of compounds 1and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized.Protease inhibition assays revealed that 12 compounds with the newscaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 newcompounds were discovered as NS2B-NS3 protease inhibitors with IC50values of 7.46 ± 1.15 to 48.59 ± 3.46 μM,and 8 compounds belonging to two different scaffolds are active tosome extent against DENV based on luciferase reporter replicon-basedassays. These novel chemical entities could serve as lead structuresfor discovering therapies against DENV. [ABSTRACT FROM AUTHOR]