United States Patent [19] Gellman et al. US006060585A [11] Patent Number: 6,060,585 [45] Date of Patent: May 9, 2000 [54] [3-POLYPEPTIDE FOLDAMERS OF WELL DEFINED SECONDARY STRUCTURE [75] Inventors: Samuel H. Gellman; Daniel H. Appella; Laurie A. Christianson; Daniel A. Klein, all of Madison, Wis.; Susanne Krauthauser, Overath, Germany; Yong Jun Chung; Xifang Wang, both of Madison, Wis. [73] Assignee: Wisconsin Alumni Research Foundation, Madison, Wis. [21] Appl. No.: 09/034,509 [22] Filed: Mar. 4, 1998 Related US. Application Data [60] Provisional application No. 60/039,905, Mar. 4, 1997. [51] Int. Cl.7 .. ....................... .. C07K 5/023 [52] US. Cl. ........................ .. 530/323; 530/324; 530/350; 530/333; 530/332; 530/331; 530/330 [58] Field of Search ................................... .. 530/323, 324, 530/330, 331, 332, 333, 350 [56] References Cited PUBLICATIONS Seebach et al. (1996), Helv. Chim. Acta. 79:913—941. Seebach et al. (1996), Helv. Chim. Acta. 79:2043—2066. Dado and Gellman (1994) J. Am. Chem. Soc. 116:1054—1062. 2.0 — Methanol 1.5 1.0 - Water 0.5 - [9) x16‘ (deg cm 2Ideclmol) ‘0.5 - Suhara et al. (1996) Tetrahedron Lett. 37:(10):1575—1578. Ellman (1996) Acc. Chem. Res. 29:132—143. Nohira et al. (1970) Bull. Chem. Soc. Jpn. 43:2230. Lam et al. (1977) Chem. 97:411—448. Herradon and Seebach (1989) Helv. Chim. Acta. 72:690—714. Tilley et al. (1992) J. Med. Chem. 35:3774—3783. Kobayashi et al. (1990) Chem. Pharm. Bull. 38:350. Blake et al. (1964) Am. Chem. Soc. 86:5293. Cooper et al. (1993) J. Chem. Soc. Perkin Trans. 1:1313. Jefford and McNulty (1994) J. Helv. Chim. Acta. 7712142. Podlech and Seebach (1995) Liebigs Ann. 1217. BodansZky et al. (1984) The Practice of Peptide Synthesis; Springer Verlag, New York. Appella et al, J. Am. Chem. Soc. 1996, vol. 118, pp. 13071—72. Karle et al., Journal Am. Chem. Soc., Oct. 1, 1997, vol. 119, N0. 39, 9087—9095. Primary Examiner—Keith D. MacMillian Assistant Examiner—T. D. Wessendorf Attorney, Agent, or Firm—DeWitt Ross & Stevens SC. [57] ABSTRACT Disclosed are [3-peptides containing cylcoalkyl, cycloalkenyl, and heterocylic substituents Which encompass the (X and [3 carbons of the peptide backbone. The [3-peptides adopt stable helical and sheet structures in both the solid state and in solution. Method of generating combinatorial libraries of peptides containing [3-peptide residues and the libraries formed thereby are disclosed. 20 Claims, 19 Drawing Sheets l l I 200 210 220 I l l l 230 240 250 260 Wavelength (nm) 0 O O O O O O H N H N H N 142* HQ‘ 2 H,+
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
United States Patent [19] Gellman et al.
US006060585A
[11] Patent Number: 6,060,585 [45] Date of Patent: May 9, 2000
[54] [3-POLYPEPTIDE FOLDAMERS OF WELL DEFINED SECONDARY STRUCTURE
[75] Inventors: Samuel H. Gellman; Daniel H. Appella; Laurie A. Christianson; Daniel A. Klein, all of Madison, Wis.; Susanne Krauthauser, Overath, Germany; Yong Jun Chung; Xifang Wang, both of Madison, Wis.
[73] Assignee: Wisconsin Alumni Research Foundation, Madison, Wis.
[21] Appl. No.: 09/034,509
[22] Filed: Mar. 4, 1998
Related US. Application Data [60] Provisional application No. 60/039,905, Mar. 4, 1997.
[58] Field of Search ................................... .. 530/323, 324,
530/330, 331, 332, 333, 350
[56] References Cited
PUBLICATIONS
Seebach et al. (1996), Helv. Chim. Acta. 79:913—941. Seebach et al. (1996), Helv. Chim. Acta. 79:2043—2066. Dado and Gellman (1994) J. Am. Chem. Soc. 116:1054—1062.
2.0 —
Methanol
1.5
1.0 -
Water 0.5 - [9) x16‘ (deg cm 2Ideclmol)
‘0.5 -
Suhara et al. (1996) Tetrahedron Lett. 37:(10):1575—1578. Ellman (1996) Acc. Chem. Res. 29:132—143. Nohira et al. (1970) Bull. Chem. Soc. Jpn. 43:2230. Lam et al. (1977) Chem. 97:411—448. Herradon and Seebach (1989) Helv. Chim. Acta. 72:690—714. Tilley et al. (1992) J. Med. Chem. 35:3774—3783. Kobayashi et al. (1990) Chem. Pharm. Bull. 38:350. Blake et al. (1964) Am. Chem. Soc. 86:5293. Cooper et al. (1993) J. Chem. Soc. Perkin Trans. 1:1313. Jefford and McNulty (1994) J. Helv. Chim. Acta. 7712142. Podlech and Seebach (1995) Liebigs Ann. 1217. BodansZky et al. (1984) The Practice of Peptide Synthesis; Springer Verlag, New York. Appella et al, J. Am. Chem. Soc. 1996, vol. 118, pp. 13071—72. Karle et al., Journal Am. Chem. Soc., Oct. 1, 1997, vol. 119, N0. 39, 9087—9095.
Primary Examiner—Keith D. MacMillian Assistant Examiner—T. D. Wessendorf Attorney, Agent, or Firm—DeWitt Ross & Stevens SC.
[57] ABSTRACT
Disclosed are [3-peptides containing cylcoalkyl, cycloalkenyl, and heterocylic substituents Which encompass the (X and [3 carbons of the peptide backbone. The [3-peptides adopt stable helical and sheet structures in both the solid state and in solution. Method of generating combinatorial libraries of peptides containing [3-peptide residues and the libraries formed thereby are disclosed.
20 Claims, 19 Drawing Sheets
l l I 200 210 220
I l l l 230 240 250 260
Wavelength (nm)
0 O O O O O O
H N H N H N 142* HQ‘ 2 H,+
U.S. Patent May 9, 2000 Sheet 1 0f 19 6,060,585
20-Helix
FIG. 1
18-Helix
U.S. Patent May 9, 2000 Sheet 2 0f 19 6,060,585
U.S. Patent May 9, 2000 Sheet 3 0f 19 6,060,585
FIG. 2B
U.S. Patent May 9, 2000 Sheet 4 0f 19 6,060,585
FIG. 2C
U.S. Patent May 9, 2000 Sheet 5 0f 19 6,060,585
65 hr 32 hr 19 hr 9 hr
6 min
I h * ‘ ‘? "I"""""?"""'I“f
8 00 7.00 6 00 PPM
U.S. Patent May 9, 2000 Sheet 6 0f 19 6,060,585
‘Wm :00 .w 12
2
‘m 0
..4
O 2
Id
0 0) I‘ I3 m
1m .n
_l - i& W
Km % %@1 ‘0 v
mm 0 I0 2 0
AW _ _ _ _ _ mm
0 O 0 O 0. m m. 0. m. w m m m
m
{9% NEG mmamg H2
FIG. 4
U.S. Patent May 9, 2000 Sheet 7 0f 19 6,060,585
40000- 3 A 2 = Dimer
'- s0ooo~ .
“g 3 = Tnmer u 2o0oo~ 4 = Tetramer N
E 0 10000~
8) 4 B 0' 5
91 ~1000o~ I I I I I
190 200 210 220 250 240 250
Wavelength (nm)
U.S. Patent May 9, 2000 Sheet 8 0f 19 6,060,585
maNo mauo 0
@AQ :ZILH OCH3 H H
50 hr
39 hr
15hr
40 min
8 min
8.50 8.00 7.50 7.00
FIG. 6
U.S. Patent May 9, 2000 Sheet 11 0f 19 6,060,585
4 z Totramer 6 a Hammer 8 :- Octamar
I I I l 200
O
5
1.0
_ w s. o. o 0 AEEQQENEQ 33 .2." § _ 5. 0.
0 6 2 O 5 2 O 4 2) m n 0( Sum 29 n .w 0% 2! 2W 0 1 2