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2013 ВЕСТНИК САНКТ-ПЕТЕРБУРГСКОГО УНИВЕРСИТЕТА Сер. 4. Вып. 4
ХИМИЯ
UDC 577.112 M. I. Titov
MEDICAL PREPARATIONS BASED ON SYNTHETIC PEPTIDES
To the memory of the centennial of the Professor V. F. Martynov's birth.
During ca. three billions years of the Earth life evolution, peptides and proteins were selected by Nature as principal molecules for initiating, modulating, and controlling the processes in living organisms. Such selection is determined by a great diversity of possible structures based on only 20 amino acids, as well as by ability of peptides and proteins to include in their structures practically all other elements of Periodical Table. Peptides possess very broad spectrum of biological activities. There are hormones, neurotransmitters, growth regulating compounds, neuroprotectors, modulators of biochemical processes, as well as there are peptides controlling metabolism, functions of nuclear acids, cell processes, etc. Besides that peptides provide specific resistance of living organism to intervention of diseases that seems to be really unique property comparing with other compounds.
Chemical, physical, and, as consequence, biological properties of peptides can be easily modulated by practically unrestricted variations of their primary structures. These variations have led to the changes in such properties as toxicity, bio-distribution, cell membranes permeability, resistance relative to ferments, etc., that allows us to engage drug design providing both desirable biological activity and features of their transportation to the target organs.
A lot of thousand of biologically active peptides are known at present; each of them can be a basis for the development of new medicines. The real boom is observed last 5-7 years in the area of developing and producing the peptide based medicines; it is explained by significant achievements in contemporary design of peptide molecules, modes of their transportation, a more profound understanding of molecular dynamics, as well as undoubted successes in peptide synthesis.
Therapeutic preparations based on synthetic peptides belong to the most quickly developed class of medicines. Although peptides are only 2 % of the total market of medicines, about 50 % of the new developments belong to peptides.
If in 1990 the number of synthetic peptide pharmaceutical preparations was less than 10 (preferably the cyclic nonapeptides oxytocin and vasopressin), however, according even to
Mikhail I. Titov — Professor, Saint Petersburg State University; e-mail: [email protected]
© M.I. Titov, 2013
incomplete data, in 2010 about 60 peptide preparations were available on market, 140 new drugs were at different stages of clinical studies, and not less that 500-600 peptides were at pre-clinical testing [1, 2]. The absolute maximum of the new drugs registered by FDA (Food and Drug Administration, USA) was established in 2012, namely six new peptide structures; five of them were registered in European Union. At present 14 peptide preparations are in the final steps of clinical testing.
In 2011 the annual sales of five peptide preparations exceeded 1 billion dollars [2, 3]:
Copaxone (glatiramer acetate), $ 4.18 billion,
Lupron (leuprodin acetate), $ 2.27 billion,
Zoladex (goserelin acetate), $ 1.19 billion,
Sandostatin (octreotide acetate), $ 1.44 billion,
Victosa, $ 1.11 billion.
Besides that, the sales of two more peptide products appeared to be close to 1 billion dollars:
Byetta (exenatide), $ 0.94 billion,
Forteo (teriparatide), $ 0.95 billion.
An annual sale of all preparations registered in USA at the end of 2011 becomes to be equal 14.7 billion USA dollars.
Peptide therapeutic preparations can be used for treating different diseases, including allergy and asthma, cardiovascular diseases, diabetes, gastrointestinal disorders, violations of growth, homeostasis, immune diseases, impotency, different kinds of infections (bacterial, viral, and candidic), inflammations, obesity, varieties of tumor, violations of mineral circulations, neurological disorders, ache, etc. [4-6].
High specificity and low toxicity makes the peptide medications the "prime choice" tools.
Peptides can be used not only as active ingredients of new drugs, but as the supplements to other therapeutic preparations with the following functions:
1. transporters, which provide the drug delivery to target cells [7, 8];
2. carriers, providing the drug permeability through cell membranes [9].
One of the most considerable achievements in peptide preparations is the introducing the drugs of incretin series used in treating the diabetes.
The diabetes of type 2 is a complex progressive disease revealed for ca. 250 millions patients. It is characterized by two principal defects.
1. The defect of insulin action in skeletal muscles and liver (or, in other words, the resistance to insulin).
2. Bifunctional defect of pancreatic secretion:
a) insufficient productivity of insulin secreting P-cells,
b) increased secretion of glucagon by a-cells.
Such metabolic defects lead to chronicle hyperglycemia and dislipidemia resulted in micro- and macro- blood vessels complications. The long-term above-normal glucose level in the blood results a toxic effect on P-cells, producing the insulin, the principal regulator of glucose level that leads to the progression of a disease. Hence, the main aim of the therapy is to arrange and to support the normal glucose level. Unfortunately, for numerous patients this task cannot be solved adequately; in the result the disease progresses that requires intensifying the medical therapy and side effects connected with that. Besides that, insulin therapy increases the risk of hypoglycemia that leads to the series of heavy complications.
Incretins are peptide hormones secreted by digestive tract as a response on food and increased the insulin secretion stimulated by glucose.
At present it is known that only two hormones GIP (glucose-dependent insulinotropic polypeptides) and GLP-1 (glucagons-like peptide-1) are incretin hormones and, in pair one each other, provides the insulin effect completely [10]. Both incretins possess similar in-sulinotropic effects. The degree of their impact on insulin secretion depends on glucose concentration; as we approach the normal glucose level, the secretion of insulin is decreased.
In physiological media incretins are quickly decomposed by ferment DPP-4, which splits N-terminated dipeptides and leads to the complete loss of hormone activity. The GLP-1 half-life time in blood stream is from 60 to 90 seconds only, so its use as drug for 2 type diabetes seems to be unreal. Obviously, the drug of such predestination should be more stable. The developing of incretin analogues, more stable in the presence of peptidases and having the higher half-life time, should result to effective preparations for therapeutic glycemia controlling, that is the main task of the diabetes treating.
The first such analogue appears to be Exenatid (exendin-4). It was isolated in 1992 from the toxin of lizard Gila Monster (Heloderma suspetum). Its half-life time in the blood exceeds 2.5 hours. 13 Years after discovering, in 2005, Exenatid was registered in USA as the medicine for diabetes 2 treating under trade brand "Byetta" (Table 1). It was followed by developing the series of analogues.
The accumulated experience in the application of incretin preparations for diabetes 2 indicated good perspectives that, besides other, stimulate the search of analogues. Some of such analogues are at the stage of clinical testing at present [3].
The following advantages of incretins comparing with insulin should be fixed:
1. the application of incretins permits us practically to avoid hypoglycemia;
2. incretins reliably decrease the weight of a body;
3. the use of insulin leads to the increasing of arterial pressure, while the use of in-cretins — vise versa;
4. the preparations of incretins can retard or interrupt progressive reducing of the mass of functioned P-cells that significantly delay the disease progress.
High expectations are related to peptides as antimicrobial preparations. The dramatic escalation of resistance of the pathogens to the "classical" antibiotics (ABs) is observed last decade [11]. It makes the selection of appropriate ABs more difficult, especially in the cases of respiratory diseases constituting ca. 70 %. The highest growth of such resistance is observed in large hospitals. For some kind of infections the part of populations resistant to ABs has increased in 10 times. So, the quantity of pneumococcuses resistant to penicillin in USA is 45 %, while 25 % of them are resistant to all known antibiotics. The same is observed in European hospitals where 25 % of total epidemiological lines of bacteria are resistant to all known ABs. The rational using of ABs restricts the appearance and developing of new resistant forms of infections, but cannot interrupt this process completely. New preparations are strongly required.
The living organisms produce antimicrobial peptides (APs) as components of innate immune system. APs is the part of their prime protection level.
The synonym of APs is Host Defense Peptides, they are universal for all living forms and have been discovered in all organisms from bacterial up to human. It is a part of ancient non-specific innate immune system. APs provide the direct protection of organisms from bacteria, candides, viruses, and parasites. In addition to their antimicrobial properties, APs demonstrates other biological effects, controlling infection, inflammatory, and oncology diseases.
Such peptides are produced in sufficient amounts directly at the place of infection or inflammatory and their expression is induced by pathogens. Biological activity of each natural AP is specific and depends on the kind of protected cells.
APs resist to pathogens for millions years and there are no indications of the appearance of microbes resistant to them. The attempts to prepare mutants resistant to APs artificially have failed, as well.
The number of publications (ca. 5,500 during 2007-2008) is the best illustration of the current interest to APs. These peptides are relatively short (12-100 amino acids), as a rule positively charged, and are characterized by different primary, secondary, and tertiary structure.
Some APs are introduced into clinical practice at present (Table 8), not less than 200 APs are at various stages of pre-clinical and clinical testing. The preparation Enfuvirtide should be separately noted; in 2003 it was registered by FDA as anti-AIDS drug. This 36-mem-bered peptide is the first preparation which protects the target cells from permeating the virus inside them. Besides that, just for this peptide the large-scale synthesis based on "classical" (in solution) and solid-phase principles was elaborated [12]. As the result, the annual production of Enfuvirtide substance exceeds 2000 kg.
The general principle of cancer treating is to kill cancer cells keeping the normal tissues. It means the selective targeting and developing the drugs which can select cancer cells. Cancer cell express specific receptor proteins on their surface (plasmatic membrane); it makes possible to distinguish them from normal cells and to use these surface markers for the aimed drug transportation. Thus, a-phetoproteins receptors are expressed on the surfaces of the most of cancer cells despite of the tumor kind, while for normal cells these receptors are presented in a small amounts. Hence, the developing of molecules to be able to connect with such markers specifically is required.
The different means are used to kill cancer cells:
1. toxins,
2. radioactive materials,
3. m-RNA inhibitors (anti-sense oligonucleotides),
4. small interfering RNA (siRNA),
5. proapoptosis peptides.
The targeted transportation of drug to a selected cell means its covalent or non-covalent bonding with vector molecule. First ligands are monoclonal antibodies. However, despite of exceptionally high specificity, these vector molecules possess few principal disadvantages:
1. badly penetrate to tissues due to large molecular weight,
2. badly endocitated,
3. they are immunogenes,
4. possess numerous side effects,
5. high price.
The low molecular weight peptides seem to be the "ideal" for mentioned purposes. The investigation "structure-activity" permits us to fix the series of relatively short peptides and to create the library of peptide sequences [13] which are specific to various receptors of tumor cells. These sequences differ by their ability to connect with surface proteins having various biological functions, namely:
1. proteins-receptors,
2. receptors of growth factors,
3. molecules responsible for cell adhesion.
Thus, fibroblasts growth factor receptors (FGFR) and epidermal growth factor receptors (EGFR) very often are over-expressed in human tumors. The activation of EGFR of type 2 (Erb B-2, tyrosin-kinase) is responsible for cell surviving, proliferation and formation of metastases of numerous human tumors. Thus, peptides connected with Erb B-2 and blocked it seem to be perspective for therapy. In this way (by connecting experiments) the oligopeptide LysCysCysTyrSerLeu was revealed [14].
Multiple myeloma is responsible for 10 % of blood cancer and produces immunoglobu-lin — paraprotein or human myeloma protein (HMP). The peptides specifically connected with HMP were revealed [15, 16]. Some of them induce apoptosis of tumor cells. There are investigations to immobilize such peptides with solid support that permits us to delete the tumor cells mechanically from bone brain afterwards.
The growth of solid tumors depends on the formation of new capillaries (angiogenesis). If the size of tumor exceeds ca. 2 mm, it requires formation of new blood vessels. One of therapy modes is based on the prevention or destruction of such vessels. Different expression of tumor and normal vessels on the surface of endothelial cells is an excellent target for therapy, the more that surface proteins of vessels are more "conservative" that those of cells. Besides that the blood circulations makes the access to these targets easier. The peptides were revealed, which are specifically connected with integrins, the proteins participating in angiogenesis and formation of metastases [17].
The vessel endothelial growth factor (VEGF) and its receptors play an important role in tumor angiogenesis and appearance of new vessels. The peptides inhibiting the VEGF connection with receptors were revealed [18]; it leads to the growth blockade of epithelial tumor cells. An interesting peptide — ArgArgLysArgArgArg — inhibits the growth of carcinoma of human rectum, as well as the formation of metastases.
Such vector peptides, besides the own therapeutic activity, can be used as a mean for transportation of therapeutic agents [3, 19].
The next problem after delivering the drug to a target cell is the problem of its permeability inside the cell. The general way to overcome the plasmatic membranes by macro-molecules in living organisms is endocitosis. However, as a rule, drug molecules penetrate this membrane with low efficiency. To optimize this process there are a series of so-called Protein Transduction Domen.
In 1988 it was revealed that TAT-protein, the part of protein membrane of virus HIV-1, is able to enter the cells (in cell culture experiments). The amino acid sequence 48-60 of this protein was discovered to be active. After that the series of peptide sequences, named as Cell-penetrating peptides, was revealed [9]. It is a class of short (less than 20 amino acids) cationic peptides those are able to penetrate plasmatic membranes of practically the all cells of mammals. Moreover, these peptides are able to deliver the broad spectrum of macromolecules into the cell, that makes them perspective candidates for target delivery of medicines.
Synthetic peptides (including those used for medical diagnostics) presented on the pharmaceutical markets of USA, Europe and Japan or passing the latest clinical tests are listed in Tables 1-11. There are preparations for treating diabetes (Table 1), hypertension (Table 2), cardiovascular diseases (Table 3), oncology (Table 4), osteoporosis (Table 5), gastrointestinal (Table 6), and central nervous system diseases (Table 7). The information about anti-microbial drugs (Table 8), preparations used for childbirth therapy (Table 9), enuresis (Table 10), and for aims of diagnostics (Table 11) is also included.
Diabetes
INNs Brand names Length, aa Sequences Companies Indications
Exenatide Byetta 39 H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Amylin Pharms, Eli Lilly Type 2 diabetes
Exenatide LAR 39 H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2 Amylin Pharms Eli Lilly Type 2 diabetes, Once-weekly
Liraglutide Victoza 31 H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-L-Y-Glu]-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH Novo Nordisk Obesity
Pramlintide Syinlin 37 H-Lys-c [CysAsnThrAlaThrCys] - Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr-NH2 Amylin Pharms Both type 1 and 2 diabetes
Lixisenatid 44 H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2 S anofi-A ventis/ Zealand Pharma Type 2 diabetes, Phase III
Taspoglutide 30 H-His-2-methyl-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Ti-p-Leu-Val-Lys-2-methyl-Ala-Arg-NHa Roche Type 2 diabetes, Once-weekly
Glucagon Glucagon 29 H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser- Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe- Val-Gln-Trp-Leu-Met-Asn-Thr-OH Eli Lilly, Bedford/ Novo Nordisk Hypoglycemia
PYY 36 H-Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH2 Nastech, Amylin Pharms, Merck Serono Obesity Phase III
Hypertension
INNs Brand names Length, aa Sequences Companies Indications
Enalapril maleate Renitec, Vasotec, Enam, Enap 3 (S)-l-[N-(l-ethoxycarbonyl)-3-phenylpropyl]-Ala-Pro-OH maleate Merck Sharp & Dohme, KRKA, Ranbaxy, Novartis, Teva Hypertension
Lisinopril Lisinopril, Prinivil, Zestril 3 (S)-l-[N-(l-carboxy-3-phenylpropyl]-Lys-Pro-OH AstraZeneca, Merck Sharp & Dohme, Novartis, Teva, Ranbaxy, Mylan Hypertension, Congestive heart failure
Saralasin acetate Sarenin 8 H-Sar-Arg-Val-Tyr-Val-His-Pro-Ala-OH acetate Norwich-Eaton Pharms, Procter & Gamble Hypertension
Cardiovascular Table 3
INNs Brand names Length, aa Sequences Companies Indications
Nesiritide Natrecor 32 H-SerProLysMetValGlnGlySerGly-c[CysPheGly- ArgLysMetAspArglleSerSerSerSerGlyLeuGlyCys]- LysValLeuArgArgHis-OH Scios Acute decompensated congestive heart failure
Eptifibatide Integrilin 7 C-[Mpa-homo-Arg-Gly-Asp-Trp-Pro-Cys]-NH2 Millennium Pharms, GSK, Schering-Plough Risk of acute cardiac ischemic events (death and/or myocardial infarction)
INNs Brand names Length, aa Sequences Companies Indications
Bivalirudin Angiomax, Angiox 20 H-D-PheProArgProGlyGlyGlyGlyAsnGlyAspPhe-GluGluIleProGluGluTyrLeu-OH Nicomed Pharma, The Medicines Company Stable angina, unstable angina, non-ST segment elevation myocardial infarction
Icatibant Firazyr 10 H-D-Arg-Arg-Pro-Hip-Gly-Thi-Ser-D-Tic-Oic-Arg-OH Jerini AG Acute attacks of hereditary angioedema
Rotigaptide 6 Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NHa Zealand/Wyeth Atrial fibrillation Phase III
Table 4 Oncology
INNs Brand names Length, aa Sequences Companies Indications
Bortezomib Velcade 2 Pyz-Phe-boroLeu- (OH) 2 Janssen-Cilag, Millennium Pharms Multiple myeloma, and refractory, mantle cell lymphoma
Cilengitide 5 c-[Arg-Gly-Asp-D-Phe-(N-Me)Val] Merck-Serono Treatment of glioblastoma by inhibiting angiogenesis Phase III
Buserelin acetate Bigonist, Suprefact 9 Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NH-Et Sanofi-Aventis, Merck Prostate cancer or breast cancer
Gonadorelin, LH-RH Factel, Kryptocur, Relefact, Lutrelef 10 Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 Ferring, Sanofi-Aventis, Wyeth Pharms Prostate cancer, disturbances fertility
Goserelin Zoladex 10 Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2 AstraZeneca Prostate cancer or breast cancer
INNs Brand names Length, aa Sequences Companies Indications
Endo Pharms, Roberts Pharma, Shire Prostate cancer,
Histrelin acetate Supprelin, Vantas 9 Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NH-Et Central precocious puberty
Leuprorelin Lupron, Lucrin, Depot, Eligard, Viadur 9 Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-Et Abbot, Bayer, Teva, Sanofi-Aventis, Wieth Prostate cancer or breast cancer, central precocious puberty
Central
Nafarelin Synarel, Synrelina 10 Pyr-His-Trp-Ser-Tyr-2-Nal-Leu-Arg-Pro-Gly-NH2 Pfizer, Searle precocious puberty, endometriosis, uterine fibrosis
Triptorelin Decapeptyl, Gonapeptyl, Pamorelin 10 Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2 Ferring, Beafour, Debiopharm Endometriosis, prostate cancer
Abarelix Plenaxis 10 Ac-D-2Nal-D-4chloroPhe-D-3-(31-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-D-Ala- nh2 Praecis Pharms, Speciality European Pharma Endometriosis
Cetrorelix Cetrotide 10 Ac-D-2Nal-D-4chloroPhe-D-3-(31-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2 Aeterna Zentaris, Merck-Serono Prostate cancer, disturbances fertility
Degarelix Degarelix, Firmagon 10 Ac-D-2Nal-D-4chloroPhe-D-3-(31-pyridyl)Ala-Ser- 4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe (carbamoyl)-Leu-isopropylLys-Pro-D-Ala-NH2 Ferring, Astellas Pharma Prostate cancer
Ganirelix Ganirelix, Antagon, Orgalutran 10 Ac-D-2Nal-D-4chloroPhe-D-3-(31-pyridyl)Ala-Ser-Tyr-D-(N9,N10-diethyl)-homoArg-Pro-D-Ala-NH2 Organon Endometriosis
INNs Brand names Length, aa Sequences Companies Indications
Stimuvax 25 H-SerThrAlaProProAlaHisGlyValThrSerAlaPro- AspThrArgProAlaProGlySerThrAlaProProLeu- (palmitoyl)Gly-OH Merck/ Oncothyreon Lung cancel-Phase III b
Primovax 16 H-GluAla-Arg-Pro-Ala-Leu-Leu-Thr-SerArg-Leu-Arg-Phe-Ile-Pro-Lys Pharmexa Pancreatic cancer Phase III
Melanotan-1 Scenesse 13 Ac-Ser-TyrSer-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 Clinuvel Pharmaceuticals Erythropoietic porphyries
ADH-1 Exherin 5 Ac-c(Cys-His-Ala-Val-Cys)-NH2 Adherex Technologies Malignant melanoma
MALP-25 13 S-[2,3-bispalmitoyloxy-(2R)-propyl]-Cys-Gly-Asn-Asn-Asp-Glu-Ser-Asn-Ile-Ser-Phe-Lys-Glu-Lys-OH Mbiotec Pancreatic cancer
Vx-001 9 Tyr-Leu-Phe-Phe-Tyr-Arg-Lys-Ser-Val Vaxon Biotech Lung cancel-Phase III
Octreotide Sandostatin 8 H-D-Phe-c[Cys-Phe-D-Trp-Lys-Thr-Cys]-Thr-ol Novartis, Teva, Bedford Labs, Sun Pharma Acromegaly, carcinoid syndrome
Lanreotide Somatuline 8 H-2-Nal-c[Cys-Phe-D-Trp-Lys-Val-Cys]-Thr-NH2 Beaufour Ipsen Pharma Acromegaly
Somatostatin Stilamin 14 H-AlaGly- [CysLysAsnPhePheTrpLysThrPheThrSerCys]-OH Merck-Serono Acromegaly, acute variceal bleeding
Vapreotide Octastatin, Sanvar 8 H-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH2 Debiopharm, H3 Pharma Acromegaly, acute variceal bleeding
Corticorelin Xerecept 41 H-SerGlnGluProProIleSerLeuAspLeuThrPheHis-LeuLeuArgGluValLeuGluMetThrLysAlaAspGln-LeuAlaGlnGlnAlaHisSerAsnArgLysLeuLeuAspIle-Ala-NH2 Celtic Pharma Peritumoral brain edema
Cn
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Osteoporosis
INNs Brand names Length, aa Sequences Companies Indications
Human calcitonin Cibacalcin 32 H-c- [CysGly AsnLeuSerThrCys] -MetLeuGlyThr- TyrThrGlnAspPheAsnLysPheHisThrPheProGln- ThrAlalleGlyValGlyAlaPro-NHa Novartis Postmenopausal osteoporosis, Paget's disease, hypercalcaemia
Miacalcin, Novartis, Astra-Zeneca, Sanofi-Aventis, Lafon, Zambon France, Pharmy II, Lisapharma
Calcimar,
Salmon calcitonin Acticalcin, Miacalcic, Calcitonin, Cadens, Calsin, Saleo 32 H-c-[CysSerAsnLeuSerThrCys]-ValLeuGlyLysLeu- SerGlnGluLeuHisLysLeuGlnThrTyrProArgThr- AsnThrGlySerGlyThrPro-NHa Postmenopausal osteoporosis, hypercalcaemia
Elcatonin Carbocalcitonin 31 c-[SerAsnLeuSerThrAsu]-ValLeuGlyLysLeuSerGln- GluLeuHisLysLeuGlnThrTyrProArgThrAspVal- GlyAlaGlyThrPro-NHa Gelacs Innovation Postmenopausal osteoporosis, Paget's disease, hypercalcaemia
PTH (1-34) Forteo 34 H-SerValSerGluIleGlnLeuMetHisAsnLeuGlyLys-HisLeuAsnSerMetGluArgValGluTrpLeuArgLys-LysLeuGlnAspValHisAsnPhe-OH Eli Lilly Osteoporosis
Ostabolin-C 31 H-SerValSerGluIleGlnLeuMetHisAsnLeuGlyLys-HisLeuAsnSerMetGluArgValGlu-c [TrpLeuArgLys] -LeuLeuGlnAspVal-NH2 Zelos Therapeutics Osteoporosis Phase III
Chrisalin 23 H-Ala-Gly-Tyr-Lys-Pro-Asp-Glu-Gly-Lys-Arg-Gly- Asp-Ala-Cys-Glu-Gly-Asp-Ser-Gly-Gly-Pro-Phe- Val-OH OrthoLogic Acceleration of fracture repair Phase III
Gastrointestinal
INNs Brand names Length, aa Sequences Companies Indications
Teduglutide Gattex 33 H-HisGlyAspGlySerPheSerAspGluMetAsnThrlle- LeuAspAsnLeuAlaAlaArgAspPhelleAsnTrpLeuIle- GlnThrLysIleThrAsp-OH NPS Pharm, Nycomed Short Bowel Syndrome
Delmitide 10 H-D-Arg-D-Nle-D-Nle-D-Nle-D-Arg-D-Nle-D-Nle-D-Nle-Gly-D-Tyr-NH2 Genzyme Irritable bowel syndrome
Sinapultide Surfaxin 21 H-L y sL euL euL euL euL y sL euL eu- L euL euL y sL euL euL euL euL y sL euL euL euL euL y s- OH Discovery Labs Meconium aspiration syndrome
Argipressin Pitressin 9 H-c [CysTyrPheGlnAsnCy s]-Pro ArgGly-NH 2 Monarch/King Pharms Central diabetes insipidus and gastrointestinal bleeding
Bleeding
Terlipressin Glypressin 12 H-GlyGlyGly-c[CysTyrPheGlnAsnCys]-ProLysGly- nh2 Ferring esophageal varices, Hepatorenal syndrome
Glutathion Agifutol, Glutathiol, Tathion 3 H-y-Glu-Cys-Gly-OH ProThera Hepatic insufficiency, wound healing, asthenia
CNS Table 7
INNs Brand names Length, aa Sequences Companies Indications
Glatiramer Copaxone H-(Glu, Ala, Lys, Tyr)n-OH Teva Reduction of the frequency of relapses in patients with Multiple Sclerosis
INNs Brand names Length, aa Sequences Companies Indications
Ziconotide Priait 25 [Cysl-Cysl6, Cys8-Cys20, Cysl5-Cys25]-tricyclo H-Cysl-LysGlyLysGlyAlaLysCys8-SerArgLeuMetTyrAspCysl5-Cysl6-ThrGlySerCys20-ArgSerGlyLysCys25-NH2 Elan Pharms Severe chronic pain
Taltirelin Ceredist 2 N-[(hexahydro-l-methyl-2,6-dioxo-4-pyrimidinyl)carbonyl]-His-Pro-NH2 Tanabe Seiyaku Spinocerebellar degenera- tion/ataxia
Nemifitide 5 H-4F-Phe-Hypro-Arg-Gly-Trp-NH2 Tetragenex Major depressive disorder
Cilengitide 5 c-[Arg-Gly-Asp-D-Phe-(N-Me) Val] Merck-Serono Glioblastoma
Antimicrobial Table 8
INNs Brand names Length, aa Sequences Companies Indications
Enfuvirtide Fuzeon 36 Ac-TyrThrSerLeuIleHisSerLeuIleGluGluSerGln- AsnGlnGlnGluLysAsnGluGlnGluLeuLeuGluLeu- AspLysTrpAlaSerLeuTi-pAsnTrpPhe-NH2 Roche AIDS/HIV-1 infection
Thymosin a-1 Zadaxin 28 Ac-SerAspAlaAlaValAspThrSerSerGluIleThrThr- LysAspLeuLysGluLysLysGluValValGluGluAlaGlu- Asn-OH SciClone Pharms Chronic hepatitis B, C
Pexiganan 22 H-GlylleGlyLysPheLeuLysLysAlaLysLysPheGly-LysAlaPheValLysIleLeuLysLys Genaera Diabetic foot ulcers
Omiganan 12 H-LeuArgTi-pProTi-pTrpProTrpArgArgLys-NH2 Cutanea Rosacea
Histatin 12 H-AlaLysArgHisHisGlyTyrLysArgLysPheHis-NH2 PacGen/ Demegen Candida albicans
Hematopoietic stem cell
Lactoferrin 11 H-GlyArgArgArgArgSerValGlnTrpCysAla-OH AM Pharma transplant infections, Systemic candidiasis
Labor
INNs Brand names Length, aa Sequences Companies Indications
Oxytocin Oxytocin, Pitocin, Sintocinon 9 H-c [Cys-Tyr-Ile-Gln-Asn-Cys]-Pro-Leu-Gly-NHa Abbot, Novartis, Teva APP Pharms Initiation of uterine contractions
Carbetocin Duratocin, Pabal, Lonactene 8 c-[Tyr(Me)Tle-Ghi-Asn-Cys((CH2)3C02-)]-Pro-Leu-Gly-NH2 Ferring Prevention of uterine atony
Atosiban Antocin, Tractocile 9 c-[Mpa-Tyr(Et)-Ile-Thr-Asn-Cys]-Pro-Orn-Gly- nh2 Ferring Delaying the birth in case of threat of premature birth
Table 10 Enuresis
INNs Brand names Length, aa Sequences Companies Indications
Desmopressin DDAVP, Defirin, Minirin, Stimat 9 H-c[Mpa-Tyr-Phe-Gln-Asn-Cys]-Pro-D-Arg-Gly- nh2 Ferring, Sanofi-Aventis, Hospira, Teva Central diabetes insipidus, nocturnal enuresis
Lypressin Diapid 9 H-c-[CysTyr-Phe-Gln-Asn-Cys]-Pro-Lys-Gly-NH2 Novartis Nocturnal enuresis
Phenipressin Felipressin 9 H-c-[Cys-Phe-Phe-Gln-Asn-Cys]-Pro-Lys-Gly-NH2 Globopharm Stomatitis, pharyngitis
o
Diagnostic
INNs Brand names Length, aa Sequences Companies Indications
Corticorelin Acthrel, Stimu-ACTH 41 H-SerGlnGluProProIleSerLeuAspLeuThrPheHis-LeuLeuArgGluValLeuGluMetThrLysAlaAspGln-LeuAlaGlnGlnAlaHisSerAsnArgLysLeuLeuAsp-IleAla-NHa Ferring Diagnosis of ACTH-dependent Cushings syndrome
Cosintropin, ACTH 1-24 Cortosyn, Synacthen, Cosintropin 24 H-SerTyrSerMetGluHisPheArgTrpGlyLysProVal-GlyLysLysArgArgProValLysValTyrPro-OH Novartis, Amphastar Pharms Diagnosis of adrenocortical insufficiency
Seractid ACTH Acthar 39 H-SerTyrSerMetGluHisPheArgTrpGlyLysProVal- GlyLysLysArgArgProValLysValTyrProAspAlaGly- GluAspGlnSerAlaGluAlaPheProLeuGluPhe-OH Armour Pharm Diagnosis of adrenocortical insufficiency
Ceruletide diethylamine Takus, Tymtran 10 Pyr-Chi-Asp-Tyr(0S03H)-Thr-Gly-Trp-Met-Asp-Phe-NH2 Pharmacia/ Upjohn, Farmitalia Carlo Erba Diagnosis of the functional state of the pancreas and stimulant of the gastric secretion
Sincalid K inevac 8 H-Asp-Tyr(0S03H)-Met-Gly-Trp-Met-Asp-Phe- nh2 Bracco Diagnostics Diagnosis of the functional state of the pancreas and stimulant of the gastric secretion
INNs Brand names Length, aa Sequences Companies Indications
Sermorelin Geref, Groliberin 29 H-TyrAlaAspAlallePheThrAsnSerTyrArgLysVal- LeuGlyGlnLeuSerAlaArgLysLeuLeuGlnAspIleMet- SerArg-NHa Serono, Kabi, Pharmacia Growth hormone deficiency, diagnosis evaluation of pituitary function
Somatorelin GHRH Ferring, Somatrel, Stimu-GH 44 H-TyrAlaAspAlallePheThrAsnSerTyrArgLysVal-LeuGlyGlnLeuSerAlaArgLysLeuLeuGlnAspIleMet-SerArgGluGlnGlyGluSerAsnGlnGluArgGlyAla-ArgAlaArgLeu-NH2 Ferring Diagnosis of somatotropic function of the anterior pituitary giand
Secretin (human) ChiRhoStim 27 H-HisSerAspGlyThrPheThrSerGluLeuSerArgLeu- ArgGluGlyAlaArgLeuGlnArgLeuLeuGlnGlyLeu- Val-NH2 ChiRhoClin Diagnosis of pancreatic exocrine dysfunction, and gastrinoma, Zoifinger-Eifison syndrome
Depreotid NeoTect, NeoSpect 10 ("Tc) c-[homoCys-(N-Me)PheTyr-D-TrpLysVal] + Mpa-ß-DabLysCysLys-NH2 Amersham, Nicomed Diagnosis of iung tumors
Pentetreotide OctreoScan 8 [N- (DTPA-N1-Ac)] -D-Phe-c [CysPhe-D-TrpLysThrCys] -Thr-ol + Indium-Ill Mallinckrodt, Bristol-Myers Squibb Diagnosis of primary and metastatic neuroendocrine tumors
Pentagastrin Pentagastrin Injection, Peptavlon 5 [(1,1-dimethylethoxy) carbonyl-ß-AlaTrpMetAspPhe-NH2 Cambridge Labs, Wyeth-Ayerst Labs, SERB Labs Diagnosis of the gastric secretion
Protirelin, TRH, Thyroliberin Thypinone, Thyrel TRH, Stimu TSH 3 Pyr-His-Pro-NH2 Abbot Ferring Diagnosis of thyroid function
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Статья поступила в редакцию 29 мая 2013 г.
