Gamma-conopeptides

Details Gamma-conopeptides Gamma-conopeptides

1998-12-15

2003-09-23

Nolan, Patrick J. (Department: 1644)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

25 or more amino acid residues in defined sequence

C530S357000

Reexamination Certificate

active

06624288

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to relatively short peptides about 25-40 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogs to the naturally available peptides, and which include three cyclizing disulfide linkages and one or more &ggr;-carboxyglutamate residues.
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and date and are listed alphabetically by author in the appended bibliography.
Mollusks of the genus Conus produce a venom that enables them to carry out their unique predatory lifestyle. Prey are immobilized by the venom that is injected by means of a highly specialized venom apparatus, a disposable hollow tooth that functions both in the manner of a harpoon and a hypodermic needle.
Few interactions between organisms are more striking than those between a venomous animal and its envenomated victim. Venom may be used as a primary weapon to capture prey or as a defense mechanism. Many of these venoms contain molecules directed to receptors and ion channels of neuromuscular systems.
The predatory cone snails (Conus) have developed a unique biological strategy. Their venom contains relatively small peptides that are targeted to various neuromuscular receptors and may be equivalent in their pharmacological diversity to the alkaloids of plants or secondary metabolites of microorganisms. Many of these peptides are among the smallest nucleic acid-encoded translation products having defined conformations, and as such, they are somewhat unusual. Peptides in this size range normally equilibrate among many conformations. Proteins having a fixed conformation are generally much larger.
The cone snails that produce these toxic peptides, which are generally referred to as conotoxins or conotoxin peptides, are a large genus of venomous gastropods comprising approximately 500 species. All cone snail species are predators that inject venom to capture prey, and the spectrum of animals that the genus as a whole can envenomate is broad. A wide variety of hunting strategies are used, however, every Conus species uses fundamentally the same basic pattern of envenomation.
Several peptides isolated from Conus venoms have been characterized. These include the &agr;-, &mgr;- and &ohgr;-conotoxins which target nicotinic acetylcholine receptors, muscle sodium channels, and neuronal calcium channels, respectively (Olivera et al., 1985). A conotoxin, TxVIIA, containing a &ggr;-carboxyglutamate residue and three disulfide bonds has been isolated (Fainzilber et al., 1991). Conopressins, which are vasopressin analogs, have also been identified (Cruz et al., 1987). In addition, peptides named conantokins have been isolated from Conus geographus and
Conus tulipa
(Mena et al., 1990; Haack et al., 1990). These peptides have unusual age-dependent physiological effects: they induce a sleep-like state in mice younger than two weeks and hyperactive behavior in mice older than 3 weeks (Haack et al., 1990). Recently, peptides named contryphans containing D-tryptophan or D-leucine residues have been isolated from Conus radiatus (U.S. Ser. No. 09/061,026), and bromo-tryptophan conopeptides have been isolated from
Conus imperialis
and
Conus radiatus
(U.S. Ser. No. 08/785,534).
Ion channels are integral plasma membrane proteins responsible for electrical activity in excitable tissues. It has been recognized that slow inward currents can influence neuronal excitability via long-lasting depolarizations of the cell membrane (Llinás, 1988). The role of slow inward currents in generating endogenous bursting behavior has been recognized in molluscan neurons (Wilson & Wachtel, 1974; Eckert & Lux, 1976; Partridge et al., 1979), and more recently in some types of mammalian neurons (Lanthorn et al., 1984; Stafstrom et al., 1985; Llinàs, 1988; Alonso & Llinàs, 1989). Changes in the slow inward currents carried by such nonspecific cation channels may play a crucial role in bursting and pacemaker activities in a variety of excitable systems, ranging from mammalian heart muscle to molluscan neurons (Partridge & Swandulla, 1988; Hoehn et al., 1993; Kits & Mansvelder, 1966; van Soest & Kits, 1997). Slow inward currents are also believed to be important in generating epileptiform bursting in regions of the brain such as the hippocampus.
It is desired to identify drugs which are useful for modulating slow inward cation channels in vertebrates involved in syndromes of clinical relevance, such as epileptic activity in hippocampus (Hoehn et al., 1993) and pacemaker potentials in heart muscle (Reuter, 1984).
SUMMARY OF THE INVENTION
This invention relates to relatively short peptides about 25-40 residues in length, which are naturally available in minute amounts in the venom of the cone snails or analogs to the naturally available peptides, and which include three cyclizing disulfide linkages and one or more &ggr;-carboxyglutamate residues.
More specifically, the present invention is directed to conopeptides having the general formula I:
Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
3
-Cys-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
4
-Cys-Cys-Xaa
5
-Xaa
6
-Xaa
7
-Xaa
8
-Cys-Xaa
2
-Xaa
2
-Xaa
2-Xaa
3
-Xaa
3
-Xaa
3
-Cys-Xaa
9
-Xaa
9
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
(SEQ ID NO: 1), wherein Xaa
1
is des-Xaa
1
or any amino acid; Xaa
2
is any amino acid; Xaa
3
is des-Xaa
3
or any amino acid; Xaa
4
is Glu &ggr;-Glu (&ggr;-carboxyglutamic acid; also referred to as Gla) or Gln; Xaa
5
is any amino acid; Xaa
6
is any amino acid; Xaa
7
is any amino acid; Xaa
8
is des-Xaa
8
or any amino acid; Xaa
9
is des-Xaa
9
or any amino acid; and Xaa
10
is des-Xaa
10
or any amino acid, with the provisos that (a) when all Xaa
10
are des-Xaa
10
, then both Xaa
9
are des-Xaa
9
or any amino acid and (b) when all Xaa
1
are des-Xaa
1
, then Xaa
5
-Xaa
6
-Xaa
7
-Xaa
8
- is not Ser-Asp-Asn.
general formula II:
Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
3
-Cys-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
4
-Cys-Cys-Xaa
5
-Xaa
6
-Xaa
7
-Xaa
8
-Cys-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
3
-Xaa
3
-Xaa
3
-Cys-Xaa
9
-Xaa
9
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
-Xaa
10
(SEQ ID NO:2), wherein Xaa
1
is des-Xaa
1
or any amino acid; Xaa
2
is any amino acid; Xaa
3
is des-Xaa
3
or any amino acid; Xaa
4
is Glu, &ggr;-Glu or Gln; Xaa
5
is Ser or Thr; Xaa
6
is any amino acid; Xaa
7
is any amino acid; Xaa
8
is des-Xaa
8
or any amino acid; Xaa
9
is des-Xaa
9
or any amino acid; and Xaa
10
is des-Xaa
10
or any amino acid, with the provisos that (a) when all Xaa
10
are des-Xaa
10
, then both Xaa
9
are des-Xaa
9
or any amino acid and (b) when all Xaa
1
are des-Xaa
1
and Xaa
5
is Ser, then Xaa
6
-Xaa
7
-Xaa
8
- is not Asp-Asn.
general formula III:
Xaa
1
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Cys-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
3
-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
2
-Xaa
2
(SEQ ID NO:3), wherein Xaa
1
is any amino acid; Xaa
2
is des-Xaa
2
or any amino acid and Xaa
3
is Glu or &ggr;-Glu.
general formula IV:
Xaa
1
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Xaa
2
-Cys-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
3
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
4
-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Xaa
1
-Xaa
1
-Xaa
1
-Cys-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
1
-Xaa
2
-Xaa
2
(SEQ ID NO:4), wherein Xaa
1
is any amino acid; Xaa
2
is des-Xaa
2
or any amino acid; Xaa
3
is Ser or Thr; and Xaa
4
is Glu or &ggr;-Glu.
or general formula V:
Xaa
1
-Xaa
1
-Xaa
2
-Cys-Xaa
3
-Xaa
3
-Xaa
4
-Phe-Xaa
3
-Xaa
3
-Cys-Thr-Xaa
3
-Xaa
3
-Ser-Xaa
5
-Cys-Cys-Ser-Asn-Ser-Cys-Asp-Gln-Thr-Tyr-Cys-Xaa
3
-Leu-Xaa
3
-Xaa
3
-Xaa
3
-Xaa
3
-Xaa
3
(SEQ ID NO:5), wherein Xaa
1
is des-Xaa
1
or any amino acid;

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