Peptide combinatorial library cyclic peptides

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

The appeal of cyclic peptides as a rich source of biologically active molecules makes the synthesis of combinatorial libraries of these compounds desirable. However, few avenues for the synthesis of large arrays of cyclic peptides exist. This is primarily caused by the difficult orthogonal deprotection requirements, which require a careful choice of synthetic strategy. For example, if a solution-phase head-to-tail cyclization is undertaken (15) (Fig. 2A), the peptide must be purified at each step of the synthesis (i.e., after synthesis of the linear, cyclized protected and after deprotection) (see Note 1). 

Eichler I, Lucka AW, Pinhla C, Houghten RA. Novel a-glucosidase inhibitors identified using multiple cyclic peptide combinatorial libraries. Mol. Diversity 1995 1 233-240. 

In an attempt to obtain shorter peptides using combinatorial libraries, Houghten and colleagues identified the highly selective tetrapeptide, D-Phe-D-Phe-D-Nle-D-Arg-NH2 (A i(K) = 1 nM, p/K > 10,000) [6, 8]. Przydzial et al. studied cyclic tetrapeptides and obtained MP-16 (Tyr-C[D-Cys-Phe-D-Cys]-NH2) with an intermediate binding affinity (K)(k) = 38.7 nM) [7]. 

The creation of drug-like molecules capable of CNS penetration from these starting points would be a challenging task. This will be made harder as room for maneuver is limited by the likely demands for isoform selectivity. For a comprehensive review of delivery of peptide and protein drugs across the blood-brain barrier, see [65]. Notably, Ghadiri and co-workers exploited this structural class and have developed an efficient synthetic access to one-bead-one-compound combinatorial libraries of cyclic tetrapeptide analogs with promising subtype selectivity [66, 67]. 

Recently, Fmoc-N-protected (3-amino acid synthons have been prepared and used for the synthesis of (3-peptides on solid phase [103]. This methodology facilitates enormously the search for new bioactive compounds, above all through the generation of combinatorial (3-peptide libraries. In this context, (3-amino acids have been used as building blocks for RGD cyclic peptides and for the synthesis of an inhibitor of human cathepsin L, previously identified by screening and deconvolution of pentapeptide amide collections [104,105]. 

The resin-bound polyamine was used as a template for the solid-phase synthesis of a range of heterocyclic compounds, such as cyclic ureas 25 and cyclic thioureas 26. This work exemplifies our ongoing efforts on the solid-phase assembly of individual acyclic and heterocyclic compounds and combinatorial libraries using short peptides as starting materials. 

Natural products are generally complex chemical structures, whether they are cyclic peptides like cyclosporin A, or complex diterpenes like paclitaxel. Inspection of the structures that are discussed in Section IV is usually enough to convince any skeptic that few of them would have been discovered without application of natural products chemistry. Recognition of this structural diversity has certainly made an impact on the design of combinatorial strategies, as exemplified by the 2 million plus compound library that was recently assembled by the Schreiber group using natural product-like structures as the initial scaffolds. 

Eichler, J., Lucka, A.W. and Houghten, R.A., Cyclic peptide template combinatorial libraries Synthesis and identification of chymotrypsin inhibitors. Peptide Res., 7 (1994) 300-307. 

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

The peptide-based phosphine ligand 105 was identified from a polymer-supported phosphine library of 75 members [154]. Enantioposition-selective desymmetrization of the meso-cyclopentenediol derivative 100 was promoted by a palladium complex of 105 to afford the cyclic carbamate 101 with 76% ee. This result demonstrated that the combinatorial approach is effective in the lead-generation stage of stereoselective catalyst development [155, 156]. The resin-supported palladium complex of Ac-D-Phg-Pro-D-Val-Pps-D-Leu-NH resin 106, which has also been developed through the combinatorial approach. 

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