1.Studies on lactam formation during coupling procedures of N alpha-N omega-protected arginine derivatives.
Cezari MH1, Juliano L. Pept Res. 1996 Mar-Apr;9(2):88-91.
We evaluated the quantity of delta-lactam generated during the synthesis of arginine-containing dipeptides using Z-Arg(Tos)-OH, Boc-Arg(Tos)-OH, Fmoc-Arg(Boc)2-OH and Fmoc-Arg(Pmc)-OH and assayed several carboxyl-activating procedures for coupling the protected arginines to different amino components. We observed significant amounts of delta-lactam during the synthesis of Z-Arg(Tos)-methyl ester and Z-Arg(Tos)-amide, as well as of Boc-Arg(Tos)-chloromethyl ketone. The mixed anhydride coupling procedure and the di-Boc-protecting guanidino group induced more delta-lactam formation than any other coupling or NG-protection method. The amide, benzyl, 4-(NO2)-benzyl and methyl alpha-carboxyl-protected amino acids generated more delta-lactam than did those protected by tertbutyl or N2H2-Boc. So far it has not been possible to propose a general mechanism for delta-lactam formation or a process that completely abolishes it. Therefore, this side reaction should be considered almost inevitable.
2.A 'conovenomic' analysis of the milked venom from the mollusk-hunting cone snail Conus textile--the pharmacological importance of post-translational modifications.
Bergeron ZL1, Chun JB, Baker MR, Sandall DW, Peigneur S, Yu PY, Thapa P, Milisen JW, Tytgat J, Livett BG, Bingham JP. Peptides. 2013 Nov;49:145-58. doi: 10.1016/j.peptides.2013.09.004. Epub 2013 Sep 18.
Cone snail venoms provide a largely untapped source of novel peptide drug leads. To enhance the discovery phase, a detailed comparative proteomic analysis was undertaken on milked venom from the mollusk-hunting cone snail, Conus textile, from three different geographic locations (Hawai'i, American Samoa and Australia's Great Barrier Reef). A novel milked venom conopeptide rich in post-translational modifications was discovered, characterized and named α-conotoxin TxIC. We assign this conopeptide to the 4/7 α-conotoxin family based on the peptide's sequence homology and cDNA pre-propeptide alignment. Pharmacologically, α-conotoxin TxIC demonstrates minimal activity on human acetylcholine receptor models (100 μM, <5% inhibition), compared to its high paralytic potency in invertebrates, PD50 = 34.2 nMol kg(-1). The non-post-translationally modified form, [Pro](2,8)[Glu](16)α-conotoxin TxIC, demonstrates differential selectivity for the α3β2 isoform of the nicotinic acetylcholine receptor with maximal inhibition of 96% and an observed IC50 of 5.
