Saturday, March 21, 2009

Cyclic Peptides

Synthetic or naturally occurring peptides can be classified as linear or cyclic peptides. Cyclic peptides (CP’s) comprise those peptides where there is a bond formed, between two residues, whereby a closed loop is formed. They can be classified as homodetic ( where all bonds are true peptide bonds) and heterodetic (where there are both peptide bonds and other types of bonding,such as ester or cystine linkages) based upon the type of bonding found in them. It has been found that CP’s often have increased metabolic stability, better receptor selectivity, controlled bioavailability and increased activity profiles. Also CP’sare metabolized more slowly due to their higher resistance to chemical degradation; on the other hand, due to their hydrophobicity they are excreted more readily than their corresponding linear counterparts. Many hormones, antibiotics,antimycotics and toxins in nature present themselves as CP’s. Many of these have been isolated, their structures resolved and produced by direct synthesis. More recently there have been more CP’s found in plants, fungi, bacteria snails and a number of other marine organisms. They are useful in the study of receptor-ligand interaction due to their restricted conformation and decreased flexibility; therefore there is continous interest in finding better synthetic routes and experimenting with modifications including but not limited to ring size, side chains and amino acid substitutions. Since the amounts found in their natural sources is often very minute, total synthetic routes remain the main/only option to obtain sufficient quantities for more in depth studies and analyses. Cyclic peptides can be of the following topologies: head to tail, side chain to side chain, side chain to tail ( or head) and branched. Ring closure in side chain to side chain CP’s can be attained by disulfide or amide bond formation between sulfhydryl groups or the appropriate functionalities. Of particular interest are connotoxins, small CP’s generally less than 12 amino acids, which have the unique characteristics of possessing 6 cysteines, which form 3 specific cystine bonds, conferring them their unique activities; some of these connotoxins have been found to have affinities 100X greater than morphine (phenathrene opiod receptor agonist) making them good candidates in the pain reducing research field, as they do not appear to induce addicition

In summary CP’s remain a very active area of synthetic interest, as more and more natural occurring CP”s are found in many flora and fauna, both terrestrial and aquatic.

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