Hexapeptide inhibitor

Lutzke, R.A.P., Eppens, N.A., Weber, P.A., Houghten, R.A., and Plasterk, R.H.A. Identification of a hexapeptide inhibitor of the human immunodeficiency virus integrase protein... 

Miller, M., Geller, M., Gribskov, M., and Kent, S. B. (1997) Analysis of the structure of chemically synthesized HIV-1 protease complexed with a hexapeptide inhibitor. Part I Crystallographic refinement of 2 A data. Proteins 27, 184-194. 

This method is compatible with many functional groups and shows considerable selectivity. Phosphonic acid esters may be cleaved in the presence of carboxylic acid esters, and phosphonate methyl esters are cleaved approximately 25 times faster than the isopropyl esters. For example, the phosphonate methyl ester of the hexapeptide analogue 78 was cleaved with TMSBr to give the aspartic peptidase inhibitor 79 in 64% yield (Scheme 28). 66 ... 

You have a peptide that is a potent inhibitor of nerve conduction and you wish to obtain its primary sequence. Amino acid analysis reveals the composition to be Ala(5) Lys Phe. Reaction of the intact peptide with FDNB releases free DNP-alanine on acid hydrolysis. e-DNP-lysine (but not a-DNP-lysine) is also found. Tryptic digestion gives a tripeptide (composition Lys, Ala (2)) and a tetrapeptide (composition Ala(3), Phe). Chymotryptic digestion of the intact peptide releases a hexapeptide and free alanine. Derive the peptide sequence. 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

Fig. 7.2 Tlie crystal structure of mammalian Ser/Thr protein phosphatase-1, complexed with the toxin mycrocystin was determined at 2.1 A resolution. PPl has a single domain with a fold, distinct from that of the protein tyrosine phosphatases. The Ser/Thr protein phosphatase-1, is a metalloenzyme with two metal ions positioned at the active site with the help of a p-a-p-o-p scaffold. A dinuclear ion centre consisting of Mn2+ And Fe2+ g situated at the catalytic site that binds the phosphate moiety of the substrate. Ser/Thr phosphatases, PPl and PP2A, are inhibited by the membrane-permeable ocadaic acid and by cyclic hexapeptides, known as microcystins. The toxin molecule is depicted as a ball-and-stick structure. On the left and on the ri t, two different views of the same molecule are shown. Microcystin binds to three distinct regions of the phosphatase to the metaLbinding site, to a hydrophobic groove, and to the edge of a C-terminal groove in the vicinity of the active site. At the surface are binding sites for substrates and inhibitors. These ribbon models are reproduced vnth permission of the authors and Nature from ref. 9.

Figure 5. Stereoview of the active site region of trypsin bound to the trypsin inhibitor complex. The lys 16 sidechain extends back into the receptor cavity (cf. Figure 7 for a better view). The proton relay chain, asp 102-his 57-ser 195 arches from right to center with ser 195 appearing in the center. The partially tetrahedral geometry of the carbonyl carbon atom of lys 16 may be seen with some difficulty. The hexapeptide from the trypsin inhibitor protein (Figure 8) is drawn intensely for emphasis central H bridges are drawn as dashed vectors.

Capped hexapeptides and heptapeptides have also been reported as inhibitors of IL-8. Antileukinate (58)inhibitsthe binding of IL-8 to both receptors and blocks both neutrophil chemotaxis and activation (285). GROa and IL-8 have been shown to be necessary for growth of lung, stomach, and colon adenocarcinomas, and antileukinate will inhibit the binding of GROa to specific receptors on adenocarcinoma cell lines and block proliferation... 

Simplification of the original lead compound is especially appropriate for natural substances. This approach, known as the disjunctive approach (see Chapter 16) consists of a molecular dissection that deletes functions, structural elements, or cycles. Classical examples of disjunctive approaches are found in the pruning of the acetylcholinesterase inhibitor physostigmine to yield neostigmine and, later one, rivastigmine (Figure 19.1) or the change from somatostatin to a simplified hexapeptide. ... 

The versatility of the side-chain anchoring approach in the synthesis of head-to-tail cyclic peptides is shown by a synthesis of cyclic phos-phorylated glycopeptides. In order to obtain a constrained peptidic inhibitor of mannose 6-phosphate receptor (MPR), Franzyk et al. [40] synthesized three cyclic hexapeptides a-glycosylated with two phosphorylated o (l->2)-... 

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