Retro-Inversion Peptides That Target GIT Transport Receptors and Related Methods

Abstract

Retro-inverted forms of GIT targeting agents that target specific receptor sites in vivo and/or promote uptake of active agents and/or enhance active site delivery across the GIT into the systemic circulation are provided. These retro-inverted peptides and compositions containing these retro-inverted peptides can be used to deliver an active agent, such as a drug or a drug-containing nano- or microparticle for treatment of a condition in a subject in need of the drug, in vivo. Additionally, the invention provides antibodies which are capable of immunospecifically binding the retro-inverted peptides.

1 . A composition comprising a d-form retro-inverted peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 (ZElan144), SEQ ID NO:2 (ZElan145) and SEQ ID NO:3 (ZElan146), wherein said peptide binds to a domain of a gastro-intestinal tract transport receptor selected from the group consisting of amino acids 29-273 of human intestinal oligopeptide transporter (HPT1), amino acids 391-571 of human oligopeptide transporter (hPEPT1), amino acids 387-685 of human D2 clone (D2H), and amino acids 272-667 of human sucrase isomaltose (hSI), wherein said peptide is no more than 50 amino acid residues, bound to an material comprising an active agent, wherein said active agent treats a mammalian disease or disorder,
 wherein said mammalian disease or disorder is selected from the group consisting of hypertension, diabetes, osteoporosis, hemophilia, anemia, cancer, migraine, and angina pectoris,   wherein the active agent is a drug selected from the group consisting of a peptide, a hormone, an analgesic, an anti-migraine agent, an anti-coagulant agent, a cardiovascular agent, an anti-emetic agent, a narcotic agonist, a chelating agent, an anti-anginal agent, a chemotherapeutic agent, a sedative, an anti-neoplasitc agent, a prostaglandin, an antidiuretic agent, an anti-sense oligonucleotide, a gene, a gene-correcting hybrid oligonculeotide, a ribozyme, an aptameric oligonucleotide, a triple-helix forming oligoncuelotide, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, a DNA-modifying agent, a non-viral gene delivery system and a viral vector gene system; and/or   wherein the active agent is a drug selected from the group consisting of insulin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoiten, α-interferon, β-interferon, γ-interferon, somatropin, somatotropin, somatostatin, somatomedins, luteinizing hormone-releasing hormone, tissueplasminogen activator, growth hormone releasing hormone, oxytocin, estrdiol, growth hormones, leuprolide acetate, factor VIII, interleukins, fentanyl, sufentanil, butorphanol, buprenophrine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclophenac, naproxen, paverin, heparin, hiruden, scopolamine, ondasetron, domperidone, etoclopramide, diltiazem, clonidine, nifedipine, verapamil, isocorbide-5-mononitrate, benzodiazeines, phenothiozines, naltrexone, naloxone, deferoxamine, desmopressin, vasopressin, nitroglycerin, 5-fluorouracil, bleomycin, prostaglandins and vincristine.   
     
     
         2 . The composition of  claim 1 , wherein the material is a particle containing the active agent. 
     
     
         3 . The composition of  claim 1 , wherein the material is a slow-release device containing the active agent. 
     
     
         4 . The composition of  claim 1 , wherein the peptide is covalently or non-covalently bound to the material. 
     
     
         5 . A composition comprising a chimeric protein bound to ameterial comprising an active agent, in which the chimeric protein comprises a d-form peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 (ZElan144), SEQ ID NO:2 (ZElan145) and SEQ ID NO:3 (ZElan146) fused via a covalent bond to an amino acid sequence of a second protein, in which the active agent treats a mammalian disease or disorder, wherein said mammalian disease or disorder is selected from the group consisting of hypertension, diabetes, osteoporosis, hemophilia, anemia, cancer, migraine, and angina pectoris, wherein said peptide binds to a domain of a gastro-intestinal tract transport receptor selected from the group consisting of amino acids 29-273 of human intestinal oligopeptide transporter (HPT1), amino acids 391-571 of human oligopeptide transporter (hPEPT1), amino acids 387-685 of human D2 clone (D2H), and amino acids 272-667 of human sucrase isomaltose (hSI),
 wherein the active agent is a drug selected from the group consisting of a peptide, a hormone, an analgesic, an anti-migraine agent, an anti-coagulant agent, a cardiovascular agent, an anti-emetic agent, a narcotic agonist, a chelating agent, an anti-anginal agent, a chemotherapeutic agent, a sedative, an anti-neoplasitc agent, a prostaglandin, an antidiuretic agent, an anti-sense oligonuclaotide, a gene, a gene-correcting hybrid oligonculeotide, a ribozyme, an aptameric oligonucleotide, a triple-helix forming oligoncuelotide, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, a DNA-modifying agent, a non-viral gene delivery system and a viral vector gene system; and/or   wherein the active agent is a drug selected from the group consisting of insulin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoiten, α-interferon, β-interferon, γ-interferon, somatropin, somatotropin, somatostatin, somatomedins, luteinizing hormone-releasing hormone, tissueplasminogen activator, growth hormone releasing hormone, oxytocin, estrdiol, growth hormones, leuprolide acetate, factor VIII, interleukins, fentanyl, sufentanil, butorphanol, buprenophrine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclophenac, naproxen, paverin, heparin, hiruden, scopolamine, ondasetron, domperidone, etoclopramide, diltiazem, clonidine, nifedipine, verapamil, isocorbide-5-mononitrate, benzodiazeines, phenothiozines, naltrexone, naloxone, deferoxamine, desmopressin, vasopressin, nitroglycerin, 5-fluorouracil, bleomycin, prostaglandins and vincristine.   
     
     
         6 . A composition comprising a d-form retro-inverted peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 (ZElan144), SEQ ID NO:2 (ZElan145) and SEQ ID NO:3 (ZElan146), wherein said peptide binds to a domain of a gastro-intestinal tract transport receptor selected from the group consisting of amino acids 29-273 of human intestinal oligopeptide transporter (HPT1), amino acids 391-571 of human oligopeptide transporter (hPEPT1), amino acids 387-685 of human D2 clone (D2H), and amino acids 272-667 of human sucrase isomaltose (hSI), wherein said peptide is no more than 50 amino acid residues, non-covalently bound to a particle containing a drug, wherein the drug is selected from the group consisting of a peptide, a hormone, an analgesic, an anti-migraine agent, an anti-coagulant agent, a cardiovascular agent, an anti-emetic agent, a narcotic agonist, a chelating agent, an anti-anginal agent, a chemotherapeutic agent, a sedative, an anti-neoplasitc agent, a prostaglandin, an antidiuretic agent, an anti-sense oligonucleotide, a gene, a gene-correcting hybrid oligonculeotide, a ribozyme, an aptameric oligonucleotide, a triple-helix forming oligoncuelotide, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, a DNA-modifying agent, a non-viral gene delivery system and a viral vector gene system; and/or
 wherein the drug is selected from a group consisting of insulin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoiten, α-interferon, β-interferon, γ-interferon, somatropin, somatotropin, somatostatin, somatomedins, luteinizing hormone-releasing hormone, tissueplasminogen activator, growth hormone releasing hormone, oxytocin, estrdiol, growth hormones, leuprolide acetate, factor VIII, interleukins, fentanyl, sufentanil, butorphanol, buprenophrine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclophenac, naproxen, paverin, heparin, hiruden, scopolamine, ondasetron, domperidone, etoclopramide, diltiazem, clonidine, nifedipine, verapamil, isocorbide-5-mononitrate, benzodiazeines, phenothiozines, naltrexone, naloxone, deferoxamine, desmopressin, vasopressin, nitroglycerin, 5-fluorouracil, bleomycin, prostaglandins and vincristine.   
     
     
         7 . A composition comprising a d-form retro-inverted peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 (ZElan144), SEQ ID NO:2 (ZElan145) and SEQ ID NO:3 (ZElan146), wherein said peptide binds to a domain of a gastro-intestinal tract transport receptor selected from the group consisting of amino acids 29-273 of human intestinal oligopeptide transporter (HPT1), amino acids 391-571 of human oligopeptide transporter (hPEPT1), amino acids 387-685 of human D2 clone (D2H), and amino acids 272-667 of human sucrase isomaltose (hSI), wherein said peptide is no more than 50 amino acid residues, covalently bound to a drug, wherein the drug is selected from a group consisting of a peptide, a hormone, an analgesic, an anti-migraine agent, an anti-coagulant agent, a cardiovascular agent, an anti-emetic agent, a narcotic agonist, a chelating agent, an anti-anginal agent, a chemotherapeutic agent, a sedative, an anti-neoplasitc agent, a prostaglandin, an antidiuretic agent, an anti-sense oligonucleotide, a gene, a gene-correcting hybrid oligonculeotide, a ribozyme, an aptameric oligonucleotide, a triple-helix forming oligoncuelotide, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, a DNA-modifying agent, a non-viral gene delivery system and a viral vector gene system; and/or
 wherein the drug is selected from the group consisting of insulin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoiten, α-interferon, β-interferon, γ-interferon, somatropin, somatotropin, somatostatin, somatomedins, luteinizing hormone-releasing hormone, tissueplasminogen activator, growth hormone releasing hormone, oxytocin, estrdiol, growth hormones, leuprolide acetate, factor VIII, interleukins, fentanyl, sufentanil, butorphanol, buprenophrine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclophenac, naproxen, paverin, heparin, hiruden, scopolamine, ondasetron, domperidone, etoclopramide, diltiazem, clonidine, nifedipine, verapamil, isocorbide-5-mononitrate, benzodiazeines, phenothiozines, naltrexone, naloxone, deferoxamine, desmopressin, vasopressin, nitroglycerin, 5-fluorouracil, bleomycin, prostaglandins and vincristine.   
     
     
         8 . The composition of  claim 1  wherein said peptide increases the transport of the active agent through human or animal gastro-intestinal tissue. 
     
     
         9 . The composition of  claim 1  which targets the active agent to a selected site or selected tissue in a human or animal. 
     
     
         10 . A pharmaceutical composition comprising the composition of  claim 1  in a pharmaceutically acceptable carrier suitable for use in humans in vivo. 
     
     
         11 . A nanoparticle or microparticle formed from a composition comprising a d-form retro-inverted peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1 (ZElan144), SEQ ID NO:2 (ZElan145) and SEQ ID NO:3 (ZElan146), wherein said peptide binds to a domain of a gastro-intestinal tract transport receptor selected from the group consisting of amino acids 29-273 of human intestinal oligopeptide transporter (HPT1), amino acids 391-571 of human oligopeptide transporter (hPEPT1), amino acids 387-685 of human D2 clone (D2H), and amino acids 272-667 of human sucrase isomaltose (hSI), wherein said peptide is no more than 50 amino acid residues, wherein the nanoparticle or microparticle is a drug-loaded nanoparticle or microparticle or a drug-encapsulating nanoparticle or microparticle, wherein the drug is selected from a group consisting of a peptide, a hormone, an analgesic, an anti-migraine agent, an anti-coagulant agent, a cardiovascular agent, an anti-emetic agent, a narcotic agonist, a chelating agent, an anti-anginal agent, a chemotherapeutic agent, a sedative, an anti-neoplasitc agent, a prostaglandin, an antidiuretic agent, an anti-sense oligonucleotide, a gene, a gene-correcting hybrid oligonculeotide, a ribozyme, an aptameric oligonucleotide, a triple-helix forming oligoncuelotide, a signal transduction pathway inhibitor, a tyrosine kinase inhibitor, a DNA-modifying agent, a non-viral gene delivery system and a viral vector gene system; and/or
 wherein the drug is selected from a group consisting of insulin, calcitonin gene regulating protein, atrial natriuretic protein, colony stimulating factor, betaseron, erythropoiten, α-interferon, β-interferon, γ-interferon, somatropin, somatotropin, somatostatin, somatomedins, luteinizing hormone-releasing hormone, tissueplasminogen activator, growth hormone releasing hormone, oxytocin, estrdiol, growth hormones, leuprolide acetate, factor VIII, interleukins, fentanyl, sufentanil, butorphanol, buprenophrine, levorphanol, morphine, hydromorphone, hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclophenac, naproxen, paverin, heparin, hiruden, scopolamine, ondasetron, domperidone, etoclopramide, diltiazem, clonidine, nifedipine, verapamil, isocorbide-5-mononitrate, benzodiazeines, phenothiozines, naltrexone, naloxone, deferoxamine, desmopressin, vasopressin, nitroglycerin, 5-fluorouracil, bleomycin, prostaglandins and vincristine.   
     
     
         12 . The composition of  claim 1  wherein the active agent is insulin or leuprolide. 
     
     
         13 . The composition of  claim 5  wherein the active agent is insulin or leuprolide.