Sanwa Kagaku Kenkyusho Co., Ltd.

Nippon Paper Industries Co., Ltd.

Yuji Hayashi

Takahito Jomori

Masayasu Kurono

Kiichi Sawai

Koichi Sugita

Hiroyasu Ebinuma

Haruo Takahashi

Kenichi Tanaka

Akira Tashita

Saori Kasahara

Katsuya Fujimura

Motohiro Takeda

Mitsuhiro Makino

Yohei Kobayashi

Takahiko Mitani

Takuji Kakigami

Fumio Takaiwa

Mitsuru Oka

Masahiro Shirai

Toshiyuki Kouzaki

Masahiro Yoshida

Mitsuaki Takeuchi

Yukari Kobara

Takahiko Matani

Masao Sakairi

Takayo Murase

Toru Murase

Noriyasu Katoh

Hiroshi Yasuda

Humio Takaiwa

Takayo Yamamoto

The present invention is regarding plants and plant storage organs thereof in which GLP-1 derivatives are accumulated, and methods of producing them. The transgenic plants and plant storage organs thereof accumulate tandem repeated GLP-1 derivatives cleavable with intestinal digestive enzyme to monomeric molecules and are produced by methods comprising: integrating into vectors linked DNAs which comprise tandem repeated DNAs encoding the GLP-1 derivative with trypsin resistance in which the amino acid in the 26th position is Gln, the amino acid in the 34th position is Asn or Asp, and C-terminal consists of Arg or Lys to produce monomeric molecules; introducing the vectors into plant cells; and redifferentiating the obtained transformants. The edible transgenic plants and plant storage organs are useful for treating diabetes and can be ingested by diabetic patients.

Plant and plant storage organ having GLP-1 derivative accumulated therein and method of producing the same

The present invention provides a method for highly producing a recombinant protein in a plant storage organ and a GLP-1 derivative. The plant storage organ in which the recombinant protein is highly produced is obtained by transformation with the use of a vector which comprises a recombinant protein gene, a cytokinin-related gene, a drug-resistant gene and a removable DNA element, in which the cytokinin-related gene and the drug-resistant gene exist in the positions so that they can behave together with the DNA element, while the recombinant protein to be expressed in the plant storage organ exists in the position so that it would not behave together with the DNA element. The GLP-1 is produced by using the method, and a derivative having been stabilized against enzymatic digestion is further provided.

GLP-1 derivative

A dipeptidyl peptidase IV inhibitor which is satisfactory in respect of activity, stability and safety and has an excellent action as a pharmaceutical agent. A compound represented by the following general formula or a pharmaceutically acceptable salt thereof: wherein Rand Reach represents hydrogen, an optionally substituted C1-6 alkyl group, or &#x2014;COORwhereupon Rrepresents hydrogen or an optionally substituted C1-6 alkyl group, or R, R, and a carbon atom together represent a 3- to 6-membered cycloalkyl group, Rrepresents hydrogen or an optionally substituted C6-10 aryl group, Rrepresents a hydrogen or a cyano group, D represents &#x2014;CONR-, &#x2014;CO&#x2014; or &#x2014;NRCO&#x2014;, Rrepresents hydrogen or an optionally substituted C1-6 alkyl group, E represents &#x2014;(CH)&#x2014; whereupon m is 1 to 3, &#x2014;CHOCH&#x2014;, or &#x2014;SCH&#x2014;, n is 0 to 3, and A represents an optionally substituted bicyclic heterocyclic group or bicyclic hydrocarbon group.

Compound inhibiting dipeptidyl peptidase IV

A GLP-1 derivative is provided including an amino acid sequence of GLP-1 (7-35) having deletion, substitution and/or addition of one or more amino acids and having Waa-(Xaa)n-Yaa (in which Waa is Arg or Lys, Xaa is Arg or Lys, n is an integer of 0 to 14, and Yaa is Arg, Arg-NH, Lys, Lys-NHor Hse) added to the C-terminus of the peptide having a GLP-1 activity. These derivatives are highly absorbable via a mucous membrane. The GLP-1 derivative can be conferred with resistance to dipeptidyl peptidase IV by substituting amino acid 8 in its GLP-1 amino acid sequence with Ser, or with resistance to trypsin by substituting amino acids 26 and 34 with Gln and Asn, respectively. The absorption efficiency of the GLP-1 derivatives via mucous membranes can be further improved by preparing a composition using a charge-regulated fat emulsion regulated to be negatively charged thereon.

GLP-1 derivative and preparation thereof absorbable via mucous membrane

A process for the preparation of a polypeptide of the formula ##STR1## wherein A' is Pro, Gly, Asp or Ser; B' is Gly, Asn or Ser; C is Gln, Glu or Asp; D is Asn, Glu or Asp; X' is a residue of amino acid other than Met; E is Gln, Lys or Arg, and Y' is a residue of homoserine or homoserine-lactone, as well as a recombinant DNA and expression plasmid for preparing the polypeptide.

Motilin-like polypeptide and use thereof

A pharmaceutical composition for stimulating peristaltic contraction in the intestinal canal which contains a pharmaceutically acceptable carrier or excipient and an effective amount of a polypeptide, or a salt thereof, having a pharmacological activity similar to motilin. The polypeptide has the formula B.sub.1 -Z.sub.1 -A.sub.1 -Z.sub.2 -B.sub.2 -Thr-B.sub.3 -A.sub.2 -Glu-Z.sub.3 -C-Arg-X'-Gln-Glu-Lys-Glu-Arg-D-Lys-Gly-E-Y, with Z.sub.1,Z.sub.2 and Z.sub.3 each being an amino acid residue having a hydrophobic side-chain, A.sub.1 and A.sub.2 each being an amino acid residue such as Pro, Gly, Asn and Ser, B.sub.1, B.sub.2 and B.sub.3 are each an amino acid residue having a side-chain with an aromatic ring, C is Gln, Glu or Asp, D is Asn, Glu or Asp, X' is an amino acid residue other than Met, E is Gln, Lys or Arg, and Y is homoserine, homoserine-lactone or a peptide chain having amino acid residues not exceeding 10 and containing homoserine or homoserine-lactone at the C-terminal where the first amino acid of said peptide chain is other than Lys, Arg or Pro.

Motlin-like polypeptide and use thereof

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Nagoya, Japan

Yuji Hayashi