Cyclic Arg-Cly-Asp-Phe-Val peptides with either D-Pile or D-Val residues were 20-to more than IOO-fold better inhibitors of ccl1 adhesion to vitronectin and/or laminin fragment Pl when compared to a linear variant or Gly-Arg-Gly-Asp-Ser.No or only little increase in inhibitory capacity was observed for fibronectin adhesion and for the binding of platelet receptor aIIbj33 to fibrinogen. NMR studies of the two most active cyclic peptides showed for both an all-tram conformation with a PII' and y turn. Subtle conformational differences, however, exist between both peptides and may contribute to selectivity of inhibition.

The Arg-Gly-Asp (RGD) sequence is a universal cell-recognition site of various extracellular proteins that interact with integrin cell-surface receptors. In order to design low-molecular-mass RGD protein antagonists, the determination of the biologically active conformation is a prerequisite. We present a method that yields detailed insight into the steric factors which govern the binding of the ligands to their receptors by systematically scanning the conformational space accessible for the tripeptide sequence RGD. The investigation is based on the conformationally controlled design of homodetic cyclic oligopeptides and their structural determination, coupled with biological assays. For this purpose, a whole set of cyclic pentapeptides and hexapeptides has been synthesized and their three-dimensional structures in solution analyzed by modern two-dimensional NMR techniques in combination with restrained and free molecular dynamics simulations. Their biological activity was compared with that of linear GRGDS in inhibition assays of tumor cell adhesion to laminin P1 and vitronectin substrates. An up to 100-fold, and in part selective, increase in activity was observed for two cyclic pentapeptides. Most other peptides showed a decreased activity which, however, was useful to correlate activity with rather small variations in conformation.Detailed comparative studies of the systematically designed conformations and the corresponding anti-adhesive activities offer an access to lead structures for a rational indirect drug design of peptide and peptidomimetic pharmaceuticals with strong interfering activity for integrin-mediated cell -cell and cell -matrix interactions.The interactions of a variety of cell-surface receptors with extracellular matrix components cause the complexity of celladhesive and cell-migratory mechanisms of several physiologically important processes including hemostasis, thrombosis, wound healing and tumor cell invasion [l]. Interactions between adhesion receptors on cell surfaces, termed integrins [2], and extracellular glycoproteins like fibrinogen, fibronectin, vitronectin and laminin form the molecular basis of cell -cell and cell -matrix contacts [3,4]. These phenomena are linked extracellularly with adhesive interactions between those substrates and their specific receptors and intracellularly with Abbreviation. cTrt, o-chlorotritylchloride; DQF, double-quantum-filtered; Fmoc, 9-fluorenylmethoxycarbonyl; HMBCS, heteronuclear multiple bond correlation with selective pulses; HMQC, heteronuclear multiple quantum coherence; inhibitory capacity (molar concentration for 50% inhibition); MD, molecular dynamics; Mtr, 4-methoxy-2,3,6-trimethylbenzenesulfonyl; NOESY, nuclear Overhauser enhancement and exchange spectroscopy; Pmc, 2,2,5,7,8-pentamethylchroman-6-sulfonyl; ROESY, rotating frame nuclear Overhauser enhancement and exchange spectroscopy; Sasrin, 2-methoxy-4-alkoxybenzylalcohol resin; TOCSY, total correlated spectroscopy. signal transduction responses [5,6]. Hence, adhesion receptors not onl...

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A series of terpene isonitriles, isolated from marine sponges, have previously been shown to exhibit antimalarial activities. Molecular modeling studies employing 3D-QSAR with receptor modeling methodologies performed with these isonitriles showed that the modeled molecules could be used to generate a pharmacophore hypothesis consistent with the experimentally derived biological activities. It was also shown that one of the modeled compounds, diisocyanoadociane (4), as well as axisonitrile-3 (2), both of which have potent antimalarial activity, interacts with heme (FP) by forming a coordination complex with the FP iron. Furthermore, these compounds were shown to inhibit sequestration of FP into beta-hematin and to prevent both the peroxidative and glutathione-mediated destruction of FP under conditions designed to mimic the environment within the malaria parasite. By contrast, two of the modeled diterpene isonitriles, 7-isocyanoamphilecta-11(20),15-diene (12) and 7-isocyano-15-isothiocyanatoamphilecta-11(20)-ene (13), that displayed little antimalarial activity also showed little inhibitory activity in these FP detoxification assays. These studies suggest that the active isonitrile compounds, like the quinoline antimalarials, exert their antiplasmodial activity by preventing FP detoxification. Molecular dynamics simulations performed with diisocyanoadociane (4) and axisonitrile-3 (2) allowed their different binding to FP to be distinguished.