Inhibitors, bioactive peptides, examples

Exogenous ACE inhibitors having an antihypertensive effect in vivo were first discovered in snake venom (Ondetti et al., 1971). Afterwards, various ACE-inhibitors have been found from enzymatic hydrolysates and related synthetic peptides of food proteins. These food proteins include such as bovine and human casein and whey, zein, gelatin, yeast and corn (Ariyoshi, 1993 Yamamoto, 1997 FitzGerald andMeisel, 2000 Pihlanto-Leppala, 2001). So far, ACE-inhibitory peptides are the most commonly known group of bioactive peptides of food protein origin. Some examples of these peptides are presented in Table III. 

Fluorine, due to its extremely high electronegativity, has a considerable electronic effect on its neighboring groups in a molecule. For example, the introduction of a difluoromeftylene moiety into a bioactive peptide has 1 to the discovery of potent competitive and reversible protease inhibitors mimicking the transition state for amide bond cleavage such as HIV protease and renin inhibitors (17-21). 

Marine sponges contain a host of bioactive compounds, particularly small molecules, and also contain a range of peptides that are non-ribosomally synthesised, often containing non-native amino acids. However, there are examples of peptides of ribosomal origin, including, for example, asteropine A isolated from the sponge Asteropus simplex.133 This peptide comprises 36 residues and three disulphide bonds. It has potent sialidase inhibitory activity and thus has applications in the design of novel viral inhibitors. Structural analysis of asteropine A with NMR spectroscopy revealed a cystine-knot motif, similar to that already described for plant toxins. This observation emphasises the fact that the cystine-knot motif is extremely prevalent in disulphide-rich peptides.134 Asteropine A, discovered in 2006, was the first reported cystine-knot peptide isolated from marine invertebrates other than from cone snails, which are described in more detail below. 

The thrombin-inhibitor example demonstrates a path from the bioactive 3-D struc-tnre of a peptide to small molecules. However, unambiguous structural information on the bioactive ligand conformation needed for snch a transformation is only available in a limited nnmber of cases. In most cases, additional complementary information has to be nsed to deduce the bioactive conformation of a bonnd ligand, and thns a pharmacophore model for virtual screening or design. 

The consistency of the high levels of enantiocontrol accessible in these diazoester cyclizations is underpinned by their growing applications in enantiose-lective synthesis of bioactive molecules containing cyclopropane units. Notable examples include the preparation of multifunctional cyclopropanes as peptide isosteres for renin inhibitors (Scheme 4) [42] presqualene alcohol from farnesyl diazoacetate (Scheme 5) [43] the GABA analogue 3-azabicyclo[3.1.0]hexan-2-one from N-allyldiazoacetamide, Eq. (26) [23] and precursors of lR,3S)-cis-chrysanthemic acid and the pheromone, E-(-)-dictyopterene C (Scheme 6) [44, 45],... 

Here, we will describe three different examples of how to use bioinformatic means to design new bioactive small molecules. The first example is the identification of new thrombin inhibitors, starting from a peptide. The second example considers the search for small molecules, starting from a peptide inhibitor the identification of antagonists of the NK receptor. The third example is the search for an inhibitor of BACEl, the beta-amyloid converting enzyme, to treat morbus Alzheimer. 

Conformational restriction can be introduced into flexible peptides by a variety of methods. For example, Marshall et al. introduced a-methyl amino acid substituents into peptides as a way to decrease the conformational space available to the resulting peptide. Freidinger et al. developed a cyclic lactam moiety (23.31) that stabilized p- and y-tum structures and applied this to LH-RH (e.g. (23.32)) to show that a p-tura about residues 6-7 was compatible with activity." Conformational restriction has been applied to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett" synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin-converting enzyme (ACE) inhibitors enalapril (2333) and enalaprilat (23.34) (Fig. 23.6) in order to characterize torsion angles in the bioactive conformation. Analog (23.35) was used to constrain... 

---