Conicamides A-D: Linear Peptides with Protease Inhibitory Activity Isolated from the Red Sea Sponge Theonella conica

Guided by the serine protease inhibition assay, four novel linear peptides, conicamides A-D (1-4), were isolated from the marine sponge Theonella conica collected in two different locations in the Red Sea. Conicamides C (3) and D (4) consist of the unique α-keto-β-amino acid, keto-homo-tyrosine, and were found to inhibit the serine proteases chymotrypsin and elastase. Conicamides C (3) and D (4) are the first characterized linear peptides containing a C-terminal α-keto-amino acid. The structure elucidation of the compounds was established based on 1H and 13C 1D NMR, homo (1H-1H) and hetero (1H-13C and 1H-15N) nuclear 2D NMR experiments, and HRMS. Marfey's method was used to determine the absolute configuration of their amino acids (except tyrosine). Synthesis of conicamides A (1) and B (2) and additional analogs was used to confirm the absolute configuration of tyrosine.