Amino-terminal modified parathyroid hormone (PTH) analogs

Details Amino-terminal modified parathyroid hormone (PTH) analogs Amino-terminal modified parathyroid hormone (PTH) analogs

1999-11-23

2003-03-25

Kemmerer, Elizabeth (Department: 1647)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S012200, C514S013800, C424S001110, C424S085100, C424S198100, C530S324000, C530S300000, C530S399000, C530S388220, C530S326000

Reexamination Certificate

active

06537965

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel parathyroid hormone peptide (PTH) derivatives. In particular, the invention relates to PTH derivatives having one or more amino acid substitutions that confer PTH-1/PTH-2 receptor agonist or antagonist properties to the derivatives.
2. Description of Related Art
Full understanding of the complex biological roles of parathyroid hormone (PTH) and efforts to utilize its therapeutic potential require dissection of the multiple signaling patterns and cellular pathways of action of the hormone. PTH binds and activates specific receptors in renal and osseous target cells that also recognize PTH-related peptide (PTHrP) (Kronenberg, H., et al., “The PTH/PTHrP receptor: one receptor for two ligands,” in
Genetics of Endocrine and Metabolic Disorders
, Thakker, R., ed., Chapman & Hall, London (1997), pp. 389-420). In renal and osteoblastic cell lines, PTH triggers several parallel intracellular signaling responses, including activation of adenylyl cyclase (AC), protein kinase A (PKA), phospholipase C (PLC) and protein kinase C (PKC) and generation of second messengers such as cyclic AMP (cAMP), inositol trisphosphate (IP
3
), diacylglycerol and increased cytosolic free calcium (Ca
i
++
) (Abou-Samra, A. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 89(7):2732-2736 (1992); Azarani, A., et al.,
J. Biol. Chem
. 271(25):14931-14936(1996); Bringhurst, F. R., et al.,
Endocrinology
132(5):2090-2098 (1993); Civitelli, R., et al.,
Am. J. Physiol
. 255(5 Pt 1):E660-667 (1988); Donahue, H. J., et al.,
J. Biol. Chem
. 263:13522-13527 (1988); Dunlay, R., and Hruska, K.,
Am. J. Physiol
. 258(2 Pt 2):F223-231 (1990); Fujimori, A., et al.,
Endocrinology
128(6):3032-3039 (1991); Fujimori, A., et al.,
Endocrinology
130(1):29-36 (1992); Guo, J., et al.,
Endocrinology
136(9):3884-3891 (1995); Janulis, M., et al.,
Endocrinology
133:713-719 (1993); Jouishomme, H., et al.,
J. Bone Miner. Res
. 9(6):943-949 (1994); Juppner, H., et al.,
Science
254(5034):1024-1026 (1991); Pines, M., et al.,
Bone
18(4):381-389 (1996); Seuwen, K., et al.,
Brit. J. Pharm
. 114(8):1613-1620 (1995); Siegfried, G., et al.,
Endocrinology
136(3):1267-1275 (1995).
To date, two structurally related but distinct species of PTH receptors have been cloned (Abou-Samra, A. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 89(7):2732-2736 (1992); Usdin, T. B., et al.,
J. Biol. Chem
. 270(26):15455-15458 (1995); Schipani, E., et al.,
Endocrinology-
132(5):2157-2165 (1993)). The first of these, type A, was isolated from both bone and kidney cells and shown to transduce multiple signaling responses to PTH-(1-34) or PTHrP(1-36) when heterologously expressed in cells that lack endogenous type 1 PTH/PTHrP receptors (PTHRs) (Abou-Samra, A. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 89(7):2732-2736 (1992); Azarani, A., et al.,
J. Biol. Chem
. 271(25):14931-14936 (1996); Bringhurst, F. R., et al.,
Endocrinology
132(5):2090-2098 (1993); Guo, J., et al.,
Endocrinology
136(9):3884-3891 (1995); Pines, M., et al.,
Bone
18(4):381-389 (1996); Jobert, A.-S., et al.,
Endocrinology
138(12):5282-5292 (1997); Schneider, H., et al.,
Eur. J. Pharm
. 246(2):149-155 (1993)).
Previous efforts to define the contributions of specific regions of the PTH molecule to its binding and signaling properties have been undertaken mainly by use of complex in vivo bioassays, organ cultures, isolated cell membranes or cell lines, generally of rodent origin, that may express more than one type of endogenous PTH receptors (Janulis, M., et al.,
Endocrinology
133:713-719 (1993); Siegfried, G., et al.,
Endocrinology
136(3):1267-1275 (1995); Yamamoto, S., et al.,
Endocrinology
138:2066-2072 (1997); Jouishomme, H., et al.,
Endocrinology
130(1):53-60 (1992); Segre, G. V., et al.,
J. Biol. Chem
. 254:6980-6986 (1979); Tregear, G. W., and Potts, J. T., Jr.
Endocr. Res. Commun
. 2:561-567 (1975); Takasu, H., et al.,
Endocrinology
137(12):5537-5543 (1996); Orloff, J. J., et al.,
Am. J. Physiol
. 262(5 Pt 1):E599-607 (1992)). For example, relatively few modifications have been made to the extreme amino terminus of PTH: Synthetic [desamino-Ala-1]bPTH-(1-34) was disclosed by Tregear et al. (
Endocr. Res. Commun
. 2:561-570, page 566 (1975)), by Goltzmann et al. (
J. Biol. Chem
. 250:3199-3203, (1975)), and by Parsons et al. (Pharmacology of parathyroid hormone and some of its fragments and analogues. In: Talamage R V, Owen M, Parsons J. A. (Eds.) Calcium-Regulating Hormones. American Elsevier, New York, pp 33-39 (1975)); synthetic [desamino Ser
1
]-hPTH(1-34) was disclosed by Tregear et al. (
Endocr. Res. Commun
. 2:561-570 (1975)) and by Rixon et al. (
J. Bone and Mineral Res
. 9: 1179-1189 (1994)); synthetic 1-desamino-hPTH-(1-31) was disclosed by Rixon et al. (
J. Bone and Mineral Res
. 9: 1179-1189, (1994))and synthetic [Ala
1
]-hPTH(1-34), and [Gly
1
]-hPTH(1-34) were disclosed by Tregear et al. (
Endocr. Res. Commun
. 2:561-570, page 563 (1975)).
Early structure/function studies of bovine PTH-(1-34), performed with isolated renal membranes, identified the key role of the carboxyl(C)-terminal bPTH-(25-34) region for receptor binding and of the amino(N)-terminus (i.e., Ser
1
) for AC activation (Segre, G. V., et al.,
J. Biol. Chem
. 254:6980-6986 (1979); Tregear, G. W., and Potts, J. T., Jr.
Endocr. Res. Commun
. 2:561-567 (1975)). Later work conducted in vitro with intact renal tubules or with cultured renal or bone cells, however, indicated that N-truncated analogs such as PTH-(3-34), although unable to stimulate AC, could fully activate PKC and could regulate certain PKC-dependent distal biologic responses (Janulis, M., et al.,
Endocrinology
133:713-719 (1993); Siegfried, G., et al.,
Endocrinology
136(3):1267-1275 (1995); Jouishomme, H., et al.,
Endocrinology
130(1):53-60 (1992)). Amino-truncated analogs of PTH-(1-34) also were found to increase PLC activity or Ca
1
++
in some cells (Donahue, H. J., et al.,
J. Biol. Chem
. 263:13522-13527 (1988); Fujimori, A., et al.,
Endocrinology
128(6):3032-3039 (1991); Siegfried, G., et al.,
Endocrinology
136(3): 1267-1275 (1995)) though not in others (Reid, I. R., et al.,
Am. J. Physiol
. 253(1 Pt 1):E45-51 (1987); Tamura, T., et al.,
Biochem. Biophys., Res. Commun
. 159:1352-1358 (1989)). Studies of the signaling properties of the cloned type I PTHR have focused almost exclusively upon activation of AC, PLC or Ca
i
++
(Abou-Samra, A. B., et al.,
Proc. Natl. Acad. Sci. U.S.A
. 89(7):2732-2736 (1992); Bringhurst, F. R., et al.,
Endocrinology
132(5):2090-2098 (1993); Guo, J., et al.,
Endocrinology
136(9):3884-3891 (1995); Pines, M., et al.,
Bone
18(4):381-389 (1996); Jobert, A.-S., et al.,
Endocrinology
138(12):5282-5292 (1997); Schneider, H., et al.,
Eur. J. Pharm
. 246(2):149-155 (1993)), although stimulation of PKC and of PKC-dependent ion transport by hPTH(1-34), hPTH-(3-34) and other hPTH fragments was reported in CHO cells transfected with rat PTHR cDNA (Azarani, A., et al.,
J. Biol. Chem
. 271(25):14931-14936 (1996)).
Collectively, these observations have engendered the concept that the structural determinants for activation of AC/PKA signaling are distinct from those required for activation of PLC or PKC and that these reside, respectively, within the N- and C-terminal domains of PTH-(1-34) (Jouishomme, H., et al.,
J. Bone Miner. Res
. 9(6):943-949 (1994); Tregear, G. W., and Potts, J. T., Jr.
Endocr. Res. Commun
. 2:561-567 (1975); Whitfield, J. F., and Morley, P.
Trends Pharm. Sci
. 16(11):382-386(1995)). In particular, the region hPTH-(29-32) was identified specifically as a critical PKC activation domain (Jouishomme, H., et al.,
J. Bone Miner. Res
. 9(6):943-949 (1994); Whitfield, J. F., and Morley, P.
Trends Pharm. Sci
. 16(11):382-386 (1995)).
Compared with what is known from these studies of the rat PTHR, much less information is available regarding the structural features of human PTH required for binding t

Affiliated with

Also associated with

Rating

Amino-terminal modified parathyroid hormone (PTH) analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Amino-terminal modified parathyroid hormone (PTH) analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amino-terminal modified parathyroid hormone (PTH) analogs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3042224