No abstract

The multipin peptide synthesis procedure has been adapted to allow the synthesis of peptides at micromole loadings. The original solid pin support was replaced with a detachable crown-shaped polyethylene support with an increased surface area. In addition, the polyethylene crowns were radiation-grafted with 2-hydroxyethyl methacrylate monomer instead of acrylic acid to yield hydroxy functionalised supports with a larger concentration of polymer and hence a larger peptide capacity. Fmoc-/3-Alanine was directly esterified to the HEMA hydroxy groups with subsequent addition of a diketopiperazine-forming handle for peptide attachment. Peptides varying in length from 10 to 25 residues were assembled at a number of loadings from 1.0 to 2.2 p o l . Purity of peptides at all loadings was equal to, and in some instances superior to, that achieved on conventional solid-phase supports. 0 Munksgaard 1993.

Recent developments in multiple peptide synthesis have made it feasible to synthesize and screen large numbers of peptide analogs simultaneously. We report here a model study of large scale screening of stereoisomers of substance P with systematic d‐aminO acid replacements. Such studies are useful in exploring conformational requirements of peptide‐receptor interaction and to provide empirical information for peptide drug design. 512 stereoisomers of SP were prepared by the multipin peptide synthesis method. Receptor binding affinities of these analogs were estimated by an iterative competition assay. Results obtained form a comprehensive database on the stereochemical requirement of SP binding to central NK1 receptor. Data from analogs with single d‐amino acid replacement are consistent with those previously reported showing that SP binding is highly sensitive to the chirality change of the C‐terminal residues (Gln6‐Leu10), but less sensitive to the chirality change of the N‐terminal residues (Arg1‐Gln5). A qualitative analysis of the database by comparison of series of peptide pairs revealed a repeated pattern of affinity change with d‐amino acid replacement, suggesting a largely additive binding activity of SP from each residue. On the other hand, possible intramolecular interactions between some N‐terminal and C‐terminal residues to form an optimal binding conformation were also found. A set of 189 peptides with IC50 values less than 5 μM was subjected to an empirical QSAR analysis using a linear additive model. The relative contribution coefficients obtained agreed with the observation that the predominant contribution comes from the C‐terminal residues, suggesting considerable independency of each residue on binding to NK1 receptors. However, the possibility of interactions among residues in forming an optimal binding conformation can not be excluded as implied by a marginal fitting of the data to this model (R2= 0.61). The poor prediction of binding activity by the model used emphasizes the importance of systematic, empirical approaches in discovery and designing new peptide analogs, which is now achievable using multipeptide synthesis techniques.

A procedure has been developed for linking two terpyridineplatinum(II), Pt(tpy), chromophores by an oligopeptide chain. It relies on the use of a new reagent, succinimido 3- (triphenylmethylthio)propanoate (2), to acylate the amino end groups of an α,ω-diaminoalkane peptide. Subsequent deprotection of the sulfhydryl groups and coupling with [ (tpy )PtlICl ]CI yields the binuclear complexes in good yields. This procedure allowed the synthesis of [ ( tpy )PtS(CH2)2 CO-Gly-Gly-Gly-NH(CH2)3NHCO-(CH2)2SPt(tpy)Cl2 (5b).

Reaction of the unsaturated, 32 valence electron species [Rh2(wCO)2(wCSMeS)2] wit~ [Rh(C2~4)2(n-C5Mes)J gives the trimetal compound G'