Demeter Biotechnologies, Ltd.

Demegen, Inc.

Gordon R Julian

Jesse M Jaynes

A method of treating a wound of a mammalian subject in rneed of such treatment, to promote healing thereof, comprising administering to the subject, e.g., to the wound locus, a composition comprising a fibroblast and keratinocyte proliferatingly effective amount of an amphipathic peptide, preferably an amphipathic peptide which is antimicrobially effective at such locus. A method is also disclosed of stimulating the accelerated growth of dermal tissue in a tissue culture containing same, comprising applying to the tissue culture a fibroblast and keratinocyte proliferatingly effective amount of an amphipathic peptide, by which the dermal tissue may be grown to produce skin for skin grafting purposes, utilizing a dermal tissue culture containing dermal tissue material of a skin graft recipient of such skin. Novel amphipathic peptides suitable for use in such methods are disclosed.

Method of enhancing wound healing by stimulating fibroblast and keratinocyte growth in vivo, utilizing amphipathic peptides

A method of treating a wound of a mammalian subject in need of such treatment, to promote healing thereof, comprising administering to the subject, e.g., to the wound locus, a composition comprising a fibroblast and keratinocyte proliferatingly effective amount of an amphipathic peptide, preferably an amphipathic peptide which is antimicrobially effective at such locus. A method is also disclosed of stimulating the accelerated growth of dermal tissue in a tissue culture containing same, comprising applying to the tissue culture a fibroblast and keratinocyte proliferatingly effective amount of an amphipathic peptide, by which the dermal tissue may be grown to produce skin for skin grafting purposes, utilizing a dermal tissue culture containing dermal tissue material of a skin graft recipient of such skin. Novel amphipathic peptides suitable for use in such methods are disclosed.

Method of enhancing wound healing by stimulating fibroblast and

A non-neurotoxin, arginine residue-containing non-naturally occurring lytic peptide comprising a sequence of amino acid residues in sufficient number and arrangement to confer lytic activity to the peptide, wherein the guanido groups of the arginine residues and the .alpha.-amino group of the N-terminal amino acid are sufficiently glyoxylated to impart enhanced tryptic, chymotryptic, and aminopeptidase digestion resistance to the peptide. The compositions of the invention are suitable for in vivo administration. A method of-making the same, to impart enhanced tryptic digestion resistance thereto, comprising glyoxylating the guanido groups of the arginine residues and the .alpha.-- amino group of the N-terminal amino acid with glyoxa containing buffer for sufficient time and at sufficient conditions to glyoxylate the side chain and .alpha.-amino groups to sufficient extent to confer enhanced proteolytic digestion resistance to the peptide.

Modified arginine containing lytic peptides and method of making the

A method of treating neoplasias, including female mammalian neoplasias such as breast, cervical, uterine, and ovarian neoplasias, as well as other neoplasias including prostatic, dermal, and bronchogenic cancers, comprising delivery of an effective non-naturally occurring, non-cytologically proliferative lytic peptide to an appropriate corporeal site to effectively treat such disease state. Particlularly preferred lytic peptide agents include small (23-39 amino acids) amphipathic cationic lytic peptides from the classes of synthetic analog derivatives of mellittin, cecropin, magainin, and defensin peptides, most preferably melittic and defensin peptides from the class of synthetic analogs of melittin, cecropin, maganin, and defensin peptides, most preferably synthetic analogs of melittic and defensin peptides.

Method of combating mammalian neoplasias, and lytic peptides therefor

A method of treating pulmonary disease states, e.g., a disease state selected from the group consisting of: cystic fibrosis, neoplasias, bronchogenic cancers, pneumonia, bronchitis, bronchopulmonary viral infections, and bronchopulmonary microbial infections, comprising delivery of an amphipathic non-naturally occurring peptide to an appropriate corporeal site, e.g., pulmonary and/or gastrointestinal loci, to effectively treat such diseases. In a further specific aspect, the invention contemplates a method of treating cystic fibrosis by delivery of lytic, amphipathic non-naturally occurring peptides to pulmonary loci, thereby effecting treatment of bronchopulmonary microbial infections associated with cystic fibrosis through lysis of pathogenic bacteria. Peptides delivered to a gastrointestinal locus preferably are non-lytic, so as not to affect normal gastrointestinal flora, and preferably are chemically modified to confer enhanced proteolytic resistance for an oral method of delivery. Peptides delivered to a pulmonary locus advantageously exhibit lytic activity and do not require chemical modification for proteolytic resistance. The delivery of the peptide to a pulmonary locus may for example be effected by use of a nebulizer device.

Method of treating pulmonary disease states with non-naturally occuring

A tryptic digestion-resistant, non-naturally occurring lytic peptide comprising a sequence of amino acid residues containing mainly alanine, valine and lysine amino acid residues, wherein the .epsilon.-amino groups of the lysine residues and the .alpha.-amino group of the N-terminal amino acid are sufficiently methylated to impart enhanced tryptic, chymotryptic, and aminopeptidase digestion resistance to the peptide. The secondary conformation of the peptide is an ordered periodic structure such as an amphipathic .alpha.-helix or a .beta.-pleated sheet. The compositions of the invention are suitable for in vivo administration. A method of making the same, to impart enhanced tryptic digestion-resistance thereto, comprising reductively alkylating the .epsilon.-amino groups of the lysine residues and the .alpha.-amino group of the N-terminal amino acid with a methyl-providing reagent in the presence of an heterocyclic amine-borane reducing agent for sufficient time and at sufficient conditions to methylate the .alpha.-and .epsilon.-amino groups to sufficient extent to confer enhanced proteolytic digestion-resistance to the peptide.

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Cary, NC, United States of America

Gordon R Julian