Peptidomimetics derived from natural products

Abstract

Although much has been written in recent years about rational drug design, no drug has been designed de novo, that is, without using a natural substrate or inhibitor or screening lead as a starting point. Instead, as we have seen, medicinal chemists continue to depend upon serendipitous discovery of novel biological activities and novel chemical entities for structures on which to begin work. What rational drug design really means at present is rational drug discovery and rational optimization. These result from the application of modern structural and mechanistic biochemistry, and good synthetic chemistry, to obtain structures with the desired spectrum of biological activities. Traditionally, lead compounds were discovered in plant and animal extracts, and more recently in microorganisms and chemical libraries. These traditional approaches continue, but are augmented by advances in molecular biology, which now provide pure proteins in quantity for screening and structure determination, as well as for characterization by modern biophysical methods. Remarkably, x-ray and NMR methods can now provide the most important information needed to design new drugs, that is, the conformations of ligands bound to target proteins. Approaches to identifying possible ligands based only on the knowledge of the enzyme active site are being developed. Some of these, such as CAVEAT, have been recently reviewed. In spite of these impressive gains, de novo design of new drugs will not be achieved until we learn how to logically build specific inhibitors of a target enzyme knowing only the protein sequence of the enzyme or the amino acid sequence of the messenger substances. We have a long way to go, because by this very rigorous definition, even the successful design of a new nonpeptide drug beginning with enzyme-ligand NMR or x-ray structure constitutes rational optimization. However, as this article has illustrated, we have made great progress. Some of the current and futuristic approaches to drug design are shown in Fig. 8. Development of useful enzyme inhibitors, designed by knowing the enzyme catalytic mechanism or discovered by screening for natural inhibitors, is a very successful rational method. Discovery of receptor antagonists by screening protocols is also productive.(ABSTRACT TRUNCATED AT 400 WORDS)

The TIPP opioid peptide family: Development of ? antagonists, ? agonists, and mixed ? agonist/? antagonists

“…Interestingly, the Tyr(3Ј-I) 1 analogues of TIPP[⌿], TICP, and TIP retained ␦ antagonist properties (Table II), 26,45 suggesting that the astonishing conversion observed with TIPP upon iodination may be due to an overall conformational change rather than to a direct local effect of the iodine substituent. TIP(P) peptides are hydrophobic and structurally flexible molecules that may undergo a so-called hydrophobic collapse 46 in an aqueous environment. It is possible that subtle structural modifications, such as introduction of an iodine substituent at the 3Ј position of Tyr 1 or saturation of the Phe 3 aromatic ring may produce different patterns of aromatic ring clustering that may result in either ␦ agonist or ␦ antagonist activity, as described above.…”

Peptidomimetics – A Versatile Route to Biologically Active Compounds

“…[36] Figure 5 summarizes the most important ways to modify the backbone of peptides at different positions.…”

Chemical ecology: a view from the pharmaceutical industry.

“…The search for inhibitors of the HIV protease began with compounds that had been prepared during prior work to inhibit related proteases, notably renin, an aspartyl protease involved in blood pressure regulation (9,10). While new structures that inhibit the HIV protease have emerged from natural product screens (11,12) [one structure that inhibits aspartyl proteases, the statine moiety, had been discovered through screening bacterial natural products before the emergence of HIV (10) (9,13,14).…”

“…While new structures that inhibit the HIV protease have emerged from natural product screens (11,12) [one structure that inhibits aspartyl proteases, the statine moiety, had been discovered through screening bacterial natural products before the emergence of HIV (10) (9,13,14).…”