PSYCLO PEPTIDE,INC.

PSYCLO PEPTIDE, INC.

PSYCLO PEPTIDE, INC.

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Generic Peptide

We provide research use generic peptides as following, for bulky order upto hundred grams or above please inquire us.  Psyclo Peptide,Inc. provides sourcing service to good quality pharma-grade peptide APIs for our customers worldwide.  ...
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Cosmetic Peptides

A variety of peptides are used in cosmetics. According to their mode of action, they have been classified into four main groups: signal peptides, carrier peptides, neurotransmitter peptides and enzyme inhibitor peptides. Peptides are used...
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Services

Our Products Psyclo Peptide  is based on sophisticated numerical methods to solve complex problems in peptide chemistry and other applications. To understand the capabilities of Psyclo Peptide this section describes the various featured products which are...
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News and Events

  EVENTS 2021 New logo and frontpage has been initiated on January 30 ,2021 March 2-5, 2021 TIDES Asia (formerly AsiaTIDES) has been completely re-imagined (for 2021 only) due to the continuing pandemic. The 2021...
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Peptide-related Impurities

Peptide drugs exhibit relatively low toxicity, high biological activity and potential applications for many medical challenges compared to the most conventional drug product. Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Most peptides today are manufactured by solid-phase peptide synthesis (SPPS).

The first group of peptide-related impurities is SPPS-related: deletion and insertion of amino acids are related to inefficient Fmoc-deprotection and excess use of amino acid reagents, respectively. Fmoc-deprotection can cause racemization of amino acid residues and thus diastereomeric impurities. Inefficient deprotection of amino acid side chains results into peptide-protection adducts. Furthermore, unprotected side chains can react with a variety of reagents used in the synthesis. Oxidation of amino acid side chains and dimeric-to-oligomeric impurities were also observed. Unwanted peptide counter ions such as trifluoroacetate, originating from the SPPS itself or from additional purification treatments, may also be present in the final peptide product. Contamination of the desired peptide product by other unrelated peptides was also seen, pointing out the lack of appropriate GMP. The second impurity group results from typical peptide degradation mechanisms such as β-elimination, diketopiperazine, pyroglutamate and succinimide formation. These SPPS- and degradation-related impurity types can also found in the finished peptide drug products, which can additionally contain a third group of related impurities, i.e. the API-excipient degradation products.

J Pharm Biomed Anal
. 2014 Dec;101:2-30. doi: 10.1016/j.jpba.2014.06.012. Epub 2014 Jun 13.

 

[4-D-serine]-leuprorelin

Pyr-His-Trp-D-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt

 

[4-(O-acetyl-L-serine]-leuprorelin

Pyr-His-Trp-Ser(Ac)-Tyr-D-Leu-Leu-Arg-Pro-NHEt

 

Glycolate-Phenylalanine

 

β-Asp28-28P

Ac-1Ser-2Asp-3Ala-4Ala-5Val-6Asp-7Thr-8Ser-9Ser-10Glu-11Ile-12Thr-13Thr-14Lys-15Asp- 16Leu-17Lys-18Glu-19Lys-20Lys-21Glu-22Val-23Val-24Glu-25Glu-26Ala-27Glu28β-Asp -OH

des-Thr12-28P

Ac-1Ser-2Asp-3Ala-4Ala-5Val-6Asp-7Thr-8Ser-9Ser-10Glu-11Ile-12Thr13Thr-14Lys-15Asp-16Leu-17Lys-18Glu-19Lys-20Lys21Glu-22Val-23Val24Glu-25Glu-26Ala-27Glu -28Asn-OH

 

Oxytocin

Dimer

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Generic Peptide

We provide research use generic peptides as following, for bulky order upto hundred grams or above please inquire us.  Psyclo Peptide,Inc. provides sourcing service to good quality pharma-grade peptide APIs for our customers worldwide.

adrenomedullin-872350

 

 

 

 

 

On-Line Store

Besides, we also provide the peptides as follows,

No English Name Cas No. Scale Specification
1 Abarelix 183552-38-7 R&D In-house
2 Atosiban 90779-69-4 Commercial In-house
3 Aviptadil 40077-57-4 R&D In-house
4 Angiotensin II 4474-91-3 R&D In-house
5 Antide 112568-12-4 R&D In-house
6 Vasporessin 11000-17-2 Commercial USP
7 Buserelin Acetate 68630-75-1 Commercial EP
8 Caspofungin Acetate 179463-17-3 Commercial In-house
9 Calcitonin (Salmon) 47931-85-1 Pilot EP
10 Carbetocin 37025-55-1 Commercial In-house
11 Carperitide 89213-87-6 R&D In-house
12 Cetrorelix Acetate 120287-85-6 Pilot In-house
13 Elcatonin 57014-02-5 R&D In-house
14 Enfuvirtide 159519-65-0 R&D In-house
15 Exenatide Acetate 141758-74-9 Pilot In-house
16 Fertirelin Acetate 66002-66-2 R&D In-house
17 GLP-1(7-36) amide 107444-51-9 R&D In-house
18 GLP-1 (7-37) 106612-94-6 R&D In-house
19 Gonadorelin Acetate 71447-49-9 Pilot EP
20 Goserelin Acetate 145781-92-6 Commercial EP/USP
21 Histrelin Acetate 220810-26-4 Commercial In-house
22 Icatibant 30308-48-4 R&D In-house
23 Lanreotide Acetate 108736-35-2 R&D In-house
24 Liraglutide 204656-20-2 Pilot In-house
25 Lysipressin 50-57-7 Commercial In-house
26 Nafarelin 86220-42-0 R&D In-house
27 Oxytocin 50-56-6 Commercial EP/USP
28 Pramlintide Acetate 196078-30-5 Pilot In-house
29 Protirelin 24305-27-9 Commercial EP
30 Sincalide Acetate 25126-32-3 R&D USP
31 Somatostatin 38916-34-6 Commercial EP/Ch.P
32 Terlipressin 14636-12-5 Commercial EP/In-house
33 Teriparatide Acetate 52232-67-4 R&D In-house
34 Thymopentin Acetate 177966-81-3 Commercial Ch.P
35 Thymosin β4 Acetate 77591-33-4 R&D In-house
36 Thymalfasin 62304-98-7 Commercial Ch.P
37 Triptorelin Acetate 140194-24-7 Commercial In-house
38 Micafungin 235114-32-6 Pilot In-house
39 Linaclotide Acetate 851199-60-5 Lab In-house
40 Degarelix 214766-78-6 Pilot In-house
41 Telavacin 372151-71-8 R&D In-house
42 Oritavancin 171099-57-3 R&D In-house
43 Dalbavancin 171500-79-1 R&D In-house
400500-3176417_1920

 Cosmetic Peptide

 

Cosmeceutical research is a rapid growing area in personal care sectors, which extends from facial products to skin and body products. A forecasted report suggested that by 2018, the global market for cosmeceuticals will reach 42 billion dollars and lead to a great demand in near future. Aging is the critical factor that causes skin collagen to lose its physical appearance in many ways such as oil production decrease, dry skin, texture loss, age spots, and loose skin. Aging causes skin thinning, and the end result is wrinkle formation. This is not limited to the aged population; younger individuals exposed to various harsh environmental conditions such as infrared and ultraviolet rays, chemical pollution, and other physical stresses can also be affected. Skin aging is a complicated biochemical progression resulting from many individual intrinsic and extrinsic factors such as age, hormones and exposure to UV light. Chronologically aged skin induced by UV radiation occurs through an increase in MMPs production, including, MMP-1, MMP-2, MMP-3 and MMP-9, which causes an imbalance of collagen synthesis by the induction of collagen or by ECM degradation. The progression occurs in the epidermal and dermal layers and is mainly related to extracellular matrix (ECM) degradation. The enzymes involved in ECM degradation are matrix metalloproteinases (MMPs) such as gelatinases (MMP-2) and collagenase. Skin loses its tensile strength due to the effect of ECM degradation by MMPs. In this process, the wrinkling of skin occurs and roughness and dryness also markedly arise along with certain pigment abnormalities such as hypo- or hyper-pigmentation. Hyperpigmentation causes human skin aging and occurs as a result of both internal and external factors including those related to hormones, UV exposure, drugs, and the presence of various chemicals. Melanin biosynthesis is a pathway that appears in melanocytes.Cosmetic scientists have conducted various in vivo and in vitro studies on skin lightening agents. The key enzyme that regulates melanin synthesis is tyrosinase. Tyrosinase is a rate-limiting enzyme that converts tyrosine to melanin. Tyrosine inhibitors thus play an importance role as skin-lightening agents.

Collagen synthesis in skin fibroblasts plays a major role in skin rejuvenation. The reduction of types I and III procollagen synthesis is a critical feature of aged skin leading to skin thinning and the increased fragility of skin. Hence, the inhibition of collagen synthesis or a loss in the function of collagen results in chronologically aged skin.

Peptides have important applications in modulating of skin cell proliferation, cell migration, inflammation, angiogenesis, melanogenesis, and protein synthesis and regulation. With variations in amino acid sequence, number of amino acids and derivatives, the future of peptide based cosmeceuticals is bright.

 

Cat. No. Product CAS Sequence
1801003 SYN-AKE 823202-99-9 beta-Ala-Pro-Dab-NHBzl
1801004 Palmitoyl tripeptide-38 1447824-23-8 Lys-Met(O2)-Lys
1801008 Copper Tripeptide-34 (Ala-His-Lys)2.Cu
1801012 Palmitoyl Tripeptide-1 147732-56-7 Palmitoyl-Gly-His-Lys
1801013 Biotinoyl Tripeptide-1 299157-54-3 Biotin-Gly-His-Lys
1801015 Copper Tripeptide-1 89030-95-5 (Gly-His-Lys)2.Cu
1801016 Acetyl Tetrapeptide-3 827306-88-7 Ac-Lys-Gly-His-Lys
1801018 Acetyl Tetrapeptide-2 757942-88-4 Ac-Lys-Asp-Val-Tyr
1801019 Acety Hexapeptide-3 616204-22-9 Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2
1801020 Palmitoyl Pentapeptide-3 214047-00-4 Palmitoyl-Lys-Thr-Thr-Lys-Ser
1801021 Acetyl Octapeptide-3 868844-74-0 Ac-Glu-Glu-Met-Gln-Arg-Arg-Ala-Asp-NH2
1801027 Palmitoyl Tripeptide-5 623172-55-4 Palmitoyl-Lys-Val-Lys-OH
1801028 Acetyl Tetrapeptide-5 820959-17-9 Ac-beta-Ala-His-Ser-His
1801029 Dipeptide-2 24587-37-9 Val-Trp
1801030 Pentapeptide-18 64963-01-5 Tyr-D-Ala-Gly-Phe-Leu
1801032 VGVAPG 124861-55-8 Val-Gly-Val-Ala-Pro-Gly
1801033 Acetyl tetrapeptide-15 928007-64-1 Tyr-Pro-Phe-Phe
1801034 Palmitoyl tetrapeptide-7 221227-05-0 Palmitoyl-Gly-Gln-Pro-Arg
1801035 Pentapeptide-3 725232-44-0 Gly-Pro-Arg-Pro-Ala-NH2
1801036 Myristoyl Pentapeptide-17 959610-30-1 Myristoyl-Lys-Leu-Ala-Lys-Lys-NH2
1801038 Palmitoyl hexapeptide-12 171263-26-6 Palmitoyl-Val-Gly-Val-Ala-Pro-Gly
1801042 Thymogen 122933-59-9 Glu-Trp

Focusing on serving quality peptide chemicals

Custom Peptide Synthesis/ManufacturingProtecting Amino AcidsPEGs & ADC LinkersLinkers for SPPSResins for PeptideOther... Read More "Focusing on serving quality peptide chemicals"

Services

PE SERVICES

Our Products

Psyclo Peptide  is based on sophisticated numerical methods to solve complex problems in peptide chemistry and other applications. To understand the capabilities of Psyclo Peptide this section describes the various featured products which are used to peptide synthesis and manufacturing.

 

 

Find thousands peptides and related  products just click:

Your All-secured On-line Store:

 

On-Line Store %e5%b1%8f%e5%b9%95%e5%bf%ab%e7%85%a7-2016-12-07-21-56-57

Our Services

Psyclo Peptide  is dedicated to serve global clients in pharma industry,research institute,university,cosmeceutical industry and other chemistry community, for their goals to aceive success. Besides various kinds of products which belongs to peptide chemistry, we also are professional in offering excellent services including consulting for peptide manufacturing , peptide purification, peptide tests analysis , sourcing for peptides and the building blocks.


 

PEBio about us-highresolution

As a emerging service provider for Pharmaceutical and Bio-tech companies, especially in peptide chemistry. We assist our customer for manuacturing no matter small quantity as miligram, to scale to hundred grams even kilos for commericialization. Our closely and seamlessly cooperated GMP-complianc facilities have been sustainabley providing manufacturing services, Psyclo Peptide can assist pharmaeutical customers’ inspection and audit to the manufacturing facilities and labs, as well as legislation affairs for entering the market and collaborative activities.

Custom Peptide Manufacturing

 

 

Psyclo Peptide has advantages in synthetic chemistry, solid support materials, purification technology, and biological drug delivery strategies have all contributed to strong growth and expanding interest in peptides, especially among large biotech and pharmaceutical companies. Research-grade peptides continues to rise at a faster pace, particularly for peptide libraries used in drug screening, target validation, epitope mapping, and structure-activity studies. Our Custom Peptide Synthesis Services use solid and solution phase chemistry employing Fmoc and t-Boc methodologies.

Price per Residue (US$)
Weight Purity
Crude  Desalt  75% 85% 90% 95% 98% 99%
5mg $3 $5 $6 $8 $10 $12 $16 $26
10mg $5 $7 $8 $10 $13 $16 $20 $29
25mg $7 $9 $12 $15 $17 $21 $25 $38
50mg $10 $12 $16 $18 $22 $27 $32 $48
100mg $12 $21 $25 $29 $34 $39 $55 $69
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Focusing on serving quality peptide chemicals

Custom Peptide Synthesis/ManufacturingProtecting Amino AcidsPEGs & ADC LinkersLinkers for SPPSResins for PeptideOther pharmaceutical intermediates(small molecules) Read More "Focusing on serving quality peptide chemicals"

Peptide Inhibitors

psc_cloud_full

Peptide Inhibitors

 

Peptide inhibitors are available in stock:

Cas#: 188968-51-6

Cat#: 1601100

 

Cas#: 1417329-24-8

Cat#: 1601101

Cas#: 1872382-47-2

Cat#: 1601103

 

Cas#: 1088715-84-7

Cat#: 1601106

 

Cas#: 1088715-84-7

Cat#: 1601109

 

 

Cas#: 1258392-53-8

Cat#: 1601104

 

Cas#: 1321514-06-0

Cat#: 1601107

 

Cas#: 1001600-56-1

Cat#: 1601102

 

Cas#: 133407-82-6

Cat#: 1601110

 

Cas#: 161552-03-0

Cat#: 1601105

Cas#: 1202402-40-1

Cat#: 1601108


Resources

ProTx II, a selective inhibitor of NaV1.7 sodium channel

2018-09-21

Introduction

ProTx II, a 30-amino acid, disulfide-rich peptide toxin, isolated from the venom of the tarantula, Thrixopelma pruriens. This toxin belongs to the inhibitory cysteine knot family and is stabilized by the disulfide frame (C1-C4, C2-C5 and C3-C6). ProTx II has the potency to inhibit the human voltage-gate sodium channel 1.7 (hNa V1.7), which is involved in nociception and might have potential as a pain therapeutic. ProTx-II inhibits Na V1.7 with an IC 50 of 0.3 nM, compared to IC 50s of 30-150 nM for other heterologously expressed Na V1 subtypes.

Biological Activity

ProTx II inhibits current by shifting the voltage dependence of activation to more depolarized potentials. It inhibits multiple sodium channel subtypes but it is reported to be ~100-fold more selective for h Na V1.7. Some studies have pointed out that ProTx-II acts by binding to the membrane-embedded voltage sensor domain of h Na V1.7, but the exact mechanism of action has not been explored clearly. Despite this difference in functional effects, ProTx-II has been proposed to bind to neurotoxin site 4 because it modifies activation. ProTx-II conforms to the inhibitory cystine knot (ICK) 2 motif, a common structural fold among spider toxins targeting ion channels. ICK peptides are defined by a 1-4, 2-5, 3-6 cystine connectivity and often have limited regular secondary structure.

Function

Owing to the well-defined three-dimensional structure and ability to inhibit voltage-gated sodium (Na V), potassium (K V) and calcium (CaV) ion channels with high potency and selectivity, disulfide-rich peptide toxins have attracted much attention as potential analgesics. In addition, voltage-gated sodium channels play important roles in action potential generation and propagation. Among them, Na V1.7 is a crucial contributor to pain sensation, and drugs that selectively target human Na V1.7 (h Na V1.7) could be ideal analgesics. Due to their stability, selectivity and potency, disulfiderich peptides such as ProTx II have been extensively characterized and are vigorously being pursued as drug leads as well as pharmacological tools.

References

1. Schmalhofer, W., Calhoun, J., Burrows, R., Bailey, T., Kohler, M. G., Weinglass, A. B., … & Priest, B. T. (2008). ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Molecular pharmacology.

2. Henriques, S. T., Deplazes, E., Lawrence, N., Cheneval, O., Chaousis, S., Inserra, M., … & Craik, D. J. (2016). Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1. 7. Journal of Biological Chemistry, jbc-M116.

3. Xiao, Y., Blumenthal, K. M., Jackson, J. O., Liang, S., & Cummins, T. R. (2010). The tarantula toxins ProTx-II and HWTX-IV differentially interact with human Nav1. 7 voltage-sensors to inhibit channel activation and inactivation. Molecular pharmacology, mol-110.


 

Inhibition of mast cell tryptase by APC 366

2018-09-21

Introduction

APC 366 [N-(1-hydroxy-2-naphthoyl)-L-arginyl-L-prolinamide], is a novel selective inhibitor of mast cell tryptase. It is a small molecule, first-generation peptidic inhibitor that has been shown efficacy in experimental models of allergic asthma, and it inhibits antigen- induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR). APC 366 showed an inhibitory potential with a Ki value of 530 nM and an IC50 value of 1400 ± 240 nM after incubation with human tryptase about 4 h.

Biological Activity

In preclinical studies, APC 366 exhibits a certain inhibitory effectiveness in a sheep model of allergic asthma. Administered by inhalation, the compound blocked allergen-induced bronchoconstriction and reversed airway hyperresponsiveness to carbachol challenge. Research has shown that APC 366 attenuates the EAR, the LAR, BHR, and accompanying influx of inflammatory leukocytes on aerosol challenge with an antigenic extract. APC 366 inactivates tryptase in a time-dependent and irreversible manner involving slow isomerization of the hydroxynaphthyl group of APC 366 followed by nucleophilic attack of a tryptase amino acid side chain to result in the formation of a nonhydrolyzable covalent adduct between inhibitor and enzyme.

Function

The mast cell is a major effector cell in acute allergic reactions. Histamine, heparin, proteases tryptase, chymase and carboxypeptidase are contained in the mast cell granules, and tryptase has been suggested as a good marker for mast cell degranulation. Tryptase has also been implicated in the pathogenesis of asthma, as elevated levels have been found in bronchoalveolar lavage (BAL) fluid from asthmatics. APC 366 has the potential role in the treatment of allergic diseases including asthma, allergic rhinitis, and allergic conjunctivitis, and human mast cell tryptase also has been proven that it can stimulate collagen synthesis in the human lung fibroblast cell line and can have both direct and indirect effects on connective tissue metabolism. Thus, as a tryptase inhibitors, APC 366 might be useful for treating fibrotic diseases such as idiopathic pulmonary fibrosis and scleroderma, in which mast cell involvement has been noted.

References:

1. Krishna, M. T., Chauhan, A., Little, L., Sampson, K., Hawksworth, R., Mant, T., … & Holgate, S. (2001). Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. Journal of Allergy and Clinical Immunology, 107(6), 1039-1045.

Sylvin, H., Dahlbäck, M., Van Der Ploeg, I., & Alving, K. (2002). The tryptase inhibitor APC‐366 reduces the acute airway response to allergen in pigs sensitized to Ascaris suum. Clinical & Experimental Allergy, 32(6), 967-971.


Function of NoxA1ds in Colon Cancer

2018-08-18

Introduction

NoxA1ds is derived from a peptide whose structure is based on a short sequence of an essential Nox subunit. It binds directly to NOX1 and displaces NOXA1 to inhibit enzymatic activity and biological function. NoxA1ds is a specific, efficacious, and cell-permeant peptidic inhibitor of Nox1 oxidase. NoxA1ds holds significant promise as a broadly useful inhibitor for testing the functional involvement of Nox1 in myriad pathologies in vitro and in vivo. Moreover, NoxA1ds could be useful as an anti-Nox1 therapeutic to ameliorate disease in its own right or as a peptidomimetic.

Pharmacologic action

NoxA1ds was applied to prepare membrane fractions before addition of fractions containing cytosolic subunits (absent in Nox4 and Nox5 preparations) to maximize its ability to inhibit the oxidase. NoxA1ds did not inhibit Nox2-derived O2- production, Nox4-derived H2O2 production, or Nox5-derived O2- production. When NoxA1ds was added to cell-free preparations of the canonical Nox1 oxidase, composed of catalytic subunit Nox1, activating subunit NOXA1 and organizing subunit NOXO1 along with Rac, NoxA1ds inhibited Nox1-derived O2- production with an IC 50 of 19 nM achieving maximum inhibition of 90% at 1.0 M. NoxA1ds does not scavenge either O2- or H2O2 and does not inhibit Nox2, Nox4, Nox5, or XO activity. NoxA1ds was treated as an isoform-specific inhibitor of Nox1. Membrane-integrated fractions from COS-Nox1 cells containing holoprotein Nox1 with its C-terminal tail were incubated with cumulative concentrations of NoxA1ds (10-12-10-5 M) before adding cytosolic fractions containing NOXA1 and NOXO1. NoxA1ds concentration-dependently inhibited O2- production with an IC50 of 20 nM. Maximal inhibition of Nox1 was achieved at 1.0 M NoxA1ds.

Function

The ability of NoxA1ds to cross the plasma membrane was tested by confocal microscopy in a human colon cancer cell line exclusively expressing Nox1 (HT-29) using FITC-labeled NoxA1ds. As the result showed, NoxA1ds significantly inhibited whole HT-29 carcinoma cell-derivedO2- generation. HT-29 cells were treated with a FITC-labeled NoxA1ds variant for 1 h before imaging. Confocal microscopy revealed that NoxA1ds permeated the cell membrane of HT-29 cells and localized to the cytoplasm. The peptide NoxA1ds is a specific inhibitor of Nox1 and this inhibition occurs via binding to the catalytic Nox1 subunit and blockade of Nox1-NOXA1 binding. NoxA1ds selectively inhibits Nox1-derived O2- production by binding Nox1 and preventing the association of Nox1 with NOXA1. NoxA1ds could potentially mimic functional sites in other proteins and thus interfere with their function. Blast was used to compare the sequence of NoxA1ds to the National Institutes of Health translated nucleotide database to determine potential nonspecific protein interactions with NoxA1ds.

References:

1. Martha Sanchez-Rodriguez1, Mariano Zacarias-Flores2, Alicia Arronte-Rosales1, and Víctor Manuel Mendoza-Nuñez. Antioxidant Effect of Hormone Therapy On Oxidative Stress and Insomnia in Posmenopausal Women. Free Radical Bio. Med. 2011 , 51 (11) :S95-S96.

2. Daniel J. Ranayhossaini, Andres I. Rodriguez, Sanghamitra Sahoo, Beibei B. Chen, Rama K. Mallampalli, Eric E. Kelley, Gabor Csanyi, Mark T. Gladwin, Guillermo Romero, and Patrick J. Pagano. Selective Recapitulation of Conserved and Nonconserved Regions of Putative NOXA1 Protein Activation Domain Confers Isoform-specific Inhibition of Nox1 Oxidase and Attenuation of Endothelial Cell Migration. J. Biological Chem. 2013, 288: 36437-36450.


Tachykinin NK2 receptor antagonist-MEN 10376

2018-09-21

Introduction

MEN 10376 (Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys-NH2) is an analogue of Neurokinin A (NKA), which has a selective affinity to NK2 tachykinin receptor. Starting from the C-terminal heptapeptide fragment of NKA, NKA (4-10) retains the same agonist activity as parent compound with increased selectivity for NK-2 receptor, and extensive structure-activity studies led to the development of a series of antagonists containing three D-Trp residues, and the MEN 10376 is the most potent compound of this series. Compared to the NKA (4-10) sequence, MEN 10376 has a sequence in which a Tyr residue is present at position 5 and a Lys residue is present at position 10.

Biological Activity

Tachykinins are a family of peptides which share the common C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. In mammals three peptides of this family, substance P, neurokinin A and neurokinin B have an established role as transmitters in the nervous systems. The researches have shown that MEN 10376 is found to be preferentially expressed in rabbit pulmonary artery and bronchus, guinea pig bronchus and human ileum and colon, and the role of the configuration of D-Trp8, D-Trp9 and of the charged residue in position 10 has been found crucial in determining the affinity and selectivity of MEN 10376. Affinities of MEN 10376, which is expressed as pA2, is 8.08 in rabbit pulmonary artery, and displays > 250-fold selectivity over NK1 (pA2 = 5.66, guinea pig ileum) and NK3 (Ki > 10 mM, guinea pig brain). MEN 10376 shows a good selectivity for the NK-2A receptor as compared to NK-2B receptor, with a 100-fold difference in affinity.

Function

NKA, a member of the tachykinin peptide family, is widely distributed in the mammalian central and peripheral nervous systems. In the latter, NKA exerts its biological effects mainly by activating the tachykinin NK2 receptor. Tachykinin NK2 receptor antagonists are potential candidates for the treatment of bronchial hyperreactivity, irritable bowel syndrome, cystitis and other pathological conditions putatively mediated by endogenous tachykinins. This has prompted the search for potent and selective NK2 receptor antagonists as drug candidates. Experiments on isolated bronchial tubes and isolated bladders in guinea pigs showed that the affinity of MEN 10376 for the NK2 receptor was much greater in the former than in the latter formulation, and it appears that MEN 10376 may be a very valuable tool to assess the biological role of tachykinins in vivo, thus extending the information to the specific role of NK2 receptors (and possibly NK2 receptor subtypes) in relevant physiological responses.

References

1. Maggi, C. A., Giuliani, S. A. N. D. R. O., Ballati, L. I. D. O., Lecci, A. L. E. S. S. A. N. D. R. O., Manzini, S. T. E. F. A. N. O., Patacchini, R. I. C. C. A. R. D. O & Giachetti, A. N. T. O. N. I. O. (1991). In vivo evidence for tachykininergic transmission using a new NK-2 receptor-selective antagonist, MEN 10,376. Journal of Pharmacology and Experimental Therapeutics, 257(3), 1172-1178.

2. Quartara, L., Patacchini, R., Giuliani, S., Renzetti, A. R., Rovero, P., & Maggi, C. A. (1992). N-terminal truncated analogs of men 10376 as tachykinin NK-2 receptor antagonists. Life sciences, 51(25), 1929-1936.

Inhibitors of Aspartic Proteases-Acetyl Pepstatin

2018-08-18

Introduction

Acetyl pepstatin, nature products of yeast fermentation, is general inhibitors of the family of aspartic proteases with the structure of Ac-Val-Val-Sta-Ala-Sta-OH, where staine (Sta) is the rare amino acid (4S,3S)-4-amino-3-hydroxy-6-methyheptanoic acid. It is a high affinity aspartic protease inhibitor for HIV-1 protease (Ki = 20 nM at pH 4.7) and HIV-2 protease (Ki = 5 nM at pH 4.7).

Biological Activity

A number of known inhibitors of aspartic proteases (PRs) were tested for their inhibitory properties against HIV-1 PR as soon as this enzyme was first isolated. One of the first ones was pepstain A, but another statine-containing compound, acetyl pepstatin, was subsequently described as a substantially more potent inhibitor of the HIV-1 PR, and the pH dependence of the binding was also demonstrated. The inhibitory effect of acetyl pepstain was found to have an apparent Ki value of 2.0×10-8 M at optimal pH. The crystallographic structure of acetyl pepstain bound to HIV-1 protease has shown that the inhibitor is bound in two approximately symmetric orientations. Bingding is stabilized by a network of hydrogen bonding and can der Waals interaction with the protease. Acetyl pepstatin is not only found to inhibit HIV-1 protease effectively, but also HIV-2 protease and 125I-H77, a renin inhibitor, from binding to other aspartyl proteases.

Function

The HIV-1 protease has been the most important target in the development of antiviral therapies against HIV-1 infection. Based on the presence of the single signature sequence aspartic acid-threonine-glycine, as well as some weak homology with the eukaryotic aspartic proteases such as pepsins, it was suggested that the HIV PR and other retroviral proteases might belong to the same family. The family of aspartyl proteases has been intensely studied in the past, and knowledge gained from studies of these enzymes has allowed early inferences as to the structure and function of the dimeric HIV PR. Moreover, the intensive effort over the past two decades to make inhibitors of human renin, a member of the family of aspartic proteases, has provided great impetus to design inhibitors of HIV PR. In fact, some of these renin inhibitors have turned out to be effective inhibitors of HIV PR as well, and have served as the starting point for drug design.

References:

  1. Krisztina Matú z1, János Mótyán1, et al. Inhibition of XMRV and HIV-1 proteases by pepstatin A and acetyl-pepstatin. Febs Journal, 2012, 279 (17), 3276-3286.
  1. Krzysztof Appelt. Crystal structures of HIV-1 protease-inhibitor complexes. Perspectives in Drug Discovery and Design, 1993, 1, 23-48.
  1. Matthew J. Todd, Ernesto Freire. The Effect of Inhibitor Binding on the Structural Stability and Cooperativity of the HIV-1 Protease. PROTEINS: Structure, Function, and Genetics, 1999, 36,147-156.
  1. Yvan Boulanger, Louis Sené;cal, Gilles Sauvé. Solution Structure of the HIV Protease Inhibitor Acetyl-pepstatin as Determined by NMR and Molecular Modeling. Journal of Biomolecular Structure & Dynamics, 1997, 14 (4), 421-428.

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