β-Peptides show biological activity
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(3-Peptides show biological activity S cientists have found in the past few years that p-peptides, com- pounds whose amino acid back- bones are one carbon-atom longer than those in natural peptides, fold into sta- ble helical, turn, and pleated-sheet con- formations in solution. Because folded p-peptides can pre- sumably form active-site structures like those in enzymes, they have been con- sidered a potential source of biologically active agents. And P-peptides are very resistant to peptidases and proteas- es, enzymes that break down peptides and proteins in the digestive system— making p-peptides promising candi- dates for the development of orally ac- tive drugs. New studies now reveal for the first time that p-peptides indeed exhibit bio- logical activity. Swiss researchers have synthesized a P-peptide with activity similar to that of the hormone somato- statin and have created a p-peptide-con- taining oligomer that binds to a key im- mune system protein. Somatostatin is an endogenous pep- tide that plays important physiological roles as a neurotransmitter and an inhibi- tor of hormone secretion. Chemistry pro- fessor Dieter Seebach and coworkers at the Swiss Federal Institute of Technology (ETH), Zurich, and Daniel Hoyer of the nervous system research team at Novar- tis Pharma, Basel, find that a cyclic p-tet- rapeptide can mimic the activity of so- matostatin [Angew. Chem. Int. Ed, 3 8 , 1223 (1999)]. The p-peptide was modeled on octreotide, a cyclic pep- tide that is used clinically as an acromegaly and intesti- nal cancer treatment. Since the atomic connec- tivity of p-peptides is differ- ent from that of natural pep- tides, "it was not at all obvi- ous that this would work," says chemistry professor Samuel H. Gellman of the University of Wisconsin, Madison, whose research interests include studies on p-peptides. "I am very en- thusiastic. This suggests that P-peptides may consti- tute general scaffolds for generating molecules that function as agonists or antag- onists of natural peptides." Cyclic (3-tetrapeptide is somatostatin mimic YY HN n »>Tr' J<„ o ' 'OH The Seebach group's P-peptide binds to somatostatin receptors with micro- molar affinity—a weak binding affinity compared to the low-nanomolar affinity of natural somatostatin. However, its af- finity is comparable with that of a glu- cose-based somatostatin analog devised earlier by a team led by chemistry pro- fessors Ralph Hirschmann and Amos B. Smith III of the University of Pennsylva- nia and K. C. Nicolaou, now at Scripps Research Institute and the University of California, San Diego [/. Am. Chem. Soc., 115, 12550 (1993)]. More recent- ly, Hirschmann, Smith, and collabora- tors reported more potent sugar-based analogs that bind to a human somato- statin receptor subtype with up to 100- nanomolar affinity [/. Med. Chem., 41, 1382 (1998)]. Their work "showed dra- matically that the peptide backbone of Somatostatin mimic modeled on octreotide Solution structure of octreotide (carbon atoms in gray) is super- imposed on model of cyclic p-peptide designed by Seebach, Hoyer, and coworkers (carbon atoms in green). Good overlap of the two structures' side chains led the researchers to synthesize the p-peptide and test it for somatostatin-like biological activity. Blue = nitrogen, red = oxygen, yellow = sulfur. somatostatin is not crucial for signal transduction," Gellman comments. 'This is presumably why p-peptides can succeed as somatostatin mimics." Seebach, research scientist Didier Rognan of ETH's pharmaceutical chem- istry group, and coworkers also have shown that hybrid peptides—oligomers whose central amino acid residues have been replaced by either p-amino or p-hy- droxy acids—bind to major histocom- patibility complex (MHC) proteins of the immune system, with affinities com- parable with those of native MHC- binding peptides \J. Med. Chem., 42, 2318 (1999)]. MHC proteins are critical immune system components that "present" anti- genic peptides to T cell receptors. Sever- al other types of hybrid oligomers have also previously been found to bind MHC proteins, but the protease resistance of P-peptides may give p-peptide-containing hybrids an advantage as lead compounds for the development of potential autoim- mune disease drugs, synthetic vaccines, and anticancer agents. In addition, Seebach and coworkers recently created a p-peptide that forms a two-stranded p-pleated sheet connected by a hairpin turn [Angew. Chem. Int. Ed., 38,1595 (1999)]. The sheet region is a repeating pattern of a p-amino acid with two neighboring side chains, one on the amino acid's a carbon and anoth- er on its p carbon. Earlier, Gellman and coworkers also synthesized a p-peptide-based sheet structure and showed that a,p-disubsti- tuted amino acids were the optimal residues to form such P-sheet "foldamers"— Gellman's term for synthet- ic oligomers with peptide- or proteinlike folding proper- ties \J. Am. Chem. Soc., 119, 11719 (1997)]. Gell- man's group has also previ- ously reported a P-peptide turn segment that forms a hairpin \J. Am. Chem. Soc, 120,10555(1998)]. The sheet-and-turn struc- ture made by Seebach and coworkers complements the earlier one created by the Gellman group in that it has the opposite dipolar ori- entation. p-Peptide sheets have a net dipole direction because all their carbonyls point the same way. Stu Borman JUNE 28,1999 C&EN 27
Transcript of β-Peptides show biological activity
(3-Peptides show biological activity
Scientists have found in the past few years that p-peptides, compounds whose amino acid back
bones are one carbon-atom longer than those in natural peptides, fold into stable helical, turn, and pleated-sheet conformations in solution.
Because folded p-peptides can presumably form active-site structures like those in enzymes, they have been considered a potential source of biologically active agents. And P-peptides are very resistant to peptidases and proteases, enzymes that break down peptides and proteins in the digestive system— making p-peptides promising candidates for the development of orally active drugs.
New studies now reveal for the first time that p-peptides indeed exhibit biological activity. Swiss researchers have synthesized a P-peptide with activity similar to that of the hormone somatostatin and have created a p-peptide-con-taining oligomer that binds to a key immune system protein.
Somatostatin is an endogenous peptide that plays important physiological roles as a neurotransmitter and an inhibitor of hormone secretion. Chemistry professor Dieter Seebach and coworkers at the Swiss Federal Institute of Technology (ETH), Zurich, and Daniel Hoyer of the nervous system research team at Novar-tis Pharma, Basel, find that a cyclic p-tet-rapeptide can mimic the activity of somatostatin [Angew. Chem. Int. Ed, 38 , 1223 (1999)]. The p-peptide was modeled on octreotide, a cyclic peptide that is used clinically as an acromegaly and intestinal cancer treatment.
Since the atomic connectivity of p-peptides is different from that of natural peptides, "it was not at all obvious that this would work," says chemistry professor Samuel H. Gellman of the University of Wisconsin, Madison, whose research interests include studies on p-peptides. "I am very enthusiastic. This suggests that P-peptides may constitute general scaffolds for generating molecules that function as agonists or antagonists of natural peptides."
Cyclic (3-tetrapeptide is somatostatin mimic
YY HN n
»>Tr' J<„ o
' 'OH
The Seebach group's P-peptide binds to somatostatin receptors with micro-molar affinity—a weak binding affinity compared to the low-nanomolar affinity of natural somatostatin. However, its affinity is comparable with that of a glucose-based somatostatin analog devised earlier by a team led by chemistry professors Ralph Hirschmann and Amos B. Smith III of the University of Pennsylvania and K. C. Nicolaou, now at Scripps Research Institute and the University of California, San Diego [/. Am. Chem. Soc., 115, 12550 (1993)]. More recently, Hirschmann, Smith, and collaborators reported more potent sugar-based analogs that bind to a human somatostatin receptor subtype with up to 100-nanomolar affinity [/. Med. Chem., 4 1 , 1382 (1998)]. Their work "showed dramatically that the peptide backbone of
Somatostatin mimic modeled on octreotide
Solution structure of octreotide (carbon atoms in gray) is superimposed on model of cyclic p-peptide designed by Seebach, Hoyer, and coworkers (carbon atoms in green). Good overlap of the two structures' side chains led the researchers to synthesize the p-peptide and test it for somatostatin-like biological activity. Blue = nitrogen, red = oxygen, yellow = sulfur.
somatostatin is not crucial for signal transduction," Gellman comments. 'This is presumably why p-peptides can succeed as somatostatin mimics."
Seebach, research scientist Didier Rognan of ETH's pharmaceutical chemistry group, and coworkers also have shown that hybrid peptides—oligomers whose central amino acid residues have been replaced by either p-amino or p-hy-droxy acids—bind to major histocompatibility complex (MHC) proteins of the immune system, with affinities comparable with those of native MHC-binding peptides \J. Med. Chem., 42 , 2318 (1999)].
MHC proteins are critical immune system components that "present" antigenic peptides to T cell receptors. Several other types of hybrid oligomers have also previously been found to bind MHC proteins, but the protease resistance of P-peptides may give p-peptide-containing hybrids an advantage as lead compounds for the development of potential autoimmune disease drugs, synthetic vaccines, and anticancer agents.
In addition, Seebach and coworkers recently created a p-peptide that forms a two-stranded p-pleated sheet connected by a hairpin turn [Angew. Chem. Int. Ed., 38,1595 (1999)]. The sheet region is a repeating pattern of a p-amino acid with two neighboring side chains, one on the amino acid's a carbon and another on its p carbon.
Earlier, Gellman and coworkers also synthesized a p-peptide-based sheet structure and showed that a,p-disubsti-
tuted amino acids were the optimal residues to form such P-sheet "foldamers"— Gellman's term for synthetic oligomers with peptide- or proteinlike folding properties \J. Am. Chem. Soc., 119, 11719 (1997)]. Gellman's group has also previously reported a P-peptide turn segment that forms a hairpin \J. Am. Chem. Soc, 120,10555(1998)].
The sheet-and-turn structure made by Seebach and coworkers complements the earlier one created by the Gellman group in that it has the opposite dipolar orientation. p-Peptide sheets have a net dipole direction because all their carbonyls point the same way.
Stu Borman
JUNE 28,1999 C&EN 27
