Peptide lead structures

The identification of non-peptidic lead structures remains a challenge. Screening of natural product extracts led to the identification of two po-lyhydroxylated biphenyls ((10a) and (10b), Figure 2.13) that show submicromolar inhibition of the viral protease [156]. A recent report discloses polyesters of glucose (11) and gallic acid (12) as micromolar inhibitors of the NS3 protease [157]. 

Pineda LF, Liebmann C, Hensellek S, Paegelow I, Steinmetzer T, Schweinitz A, Stiirze-becher J, Reissmann S. Novel non-peptide lead structures for bradykinin B2-receptor antagonists. Lett Pept Sci 2000 7 69-77. 

The hydantoin moiety has been utilized as a biostere for the peptide linkage, transforming a peptide lead into an orally available drug candidate. Therefore, an Arg-Gly-Asp-Ser tetrapeptide (18) lead structure was modified to a non-peptide RGD mimetic as an orally active fibrinogen receptor antagonist 19. ° ... 

This contribution will summarize the currently pursued approaches towards non-peptide SH2 domain antagonists and the development of promising lead structures for SH2 domain-associated disease processes. It is clearly beyond the scope of this review to provide an in-depth overview of the entire research area. 

Other compounds reported were conjugates with vasoactive intestinal peptide (VIP) and derivatives thereof [65, 67]. Based on VIP as the lead structure, it was shown that peptide conjugates with cyanine dyes could be prepared on solid cellulose supports to generate peptide libraries for drug screening and optimization [67]. 

In recent years, developments in high-throughput screening inspired many pharmaceutical companies to focus and rely on combinatorial chemistry, especially massive parallel synthesis, to find new lead structures. The employed chemistry is often simple and the concept depends on sheer numbers for success. The main research areas were heterocyclic and peptide chemistry, and the resulting structures often lacked complexity and diversity, and most importantly the chance to utilize the evolutionary advantage of natural products with their privileged structures. 

Although no structure of class II HDAC has been solved in complex with an acetylated peptide, the structure of FB188 H DAH bound to an acetate molecule, the deacetylation reaction product, showed that the acetate was bound to the Zn ion [48]. A17-A long channel was found in FB188 HDAH, leading from the bottom of the active site cavity to the protein surface, and was proposed to function as an exit tunnel for the acetate, as previously proposed for HDLP [41, 44]. 

Substitution of the terminal amine with ligating groups, such as catecholate, hydrox-amate or diketonate, lead to the formation of A-cis chiral complexes. In these structures the chiral information content is located in the amino acid bridges, instead of the macrocyclic peptide ring structure used in ferrichrome. It should be emphasized... 

The main objective of this experiment was to demonstrate that a peptide lead compound could be used in rational design of a non-peptide library. One of the natural opiates, met-enkephalin, is used as a hypothetical lead compound. The averaged frequency distribution based on four SA runs is obtained (data not shown). Based on this result, 03 had the highest frequency, and the frequencies of A4, Dll, D13, D14, D16, D2, D3, D5, and D9 are also above random expectation. Apparently, 03 appeared in all the reported active peptoids with opioid activity (cf. Table 1). Comparison of the structure of met-enkephalin (Fig. 5) with 03 indicated that 03 is similar to the side chain of tyrosine, which is the N-terminal residue of met-enkephalin. Among other building blocks found more frequently than random expectation, A4, D3, and D13 are present in the reported opioid peptoids (cf. Table 1). Thus, the SA sampling correctly identified four... 

---