Custom services to stimulate inhibitor innovationsAs a complement to these catalog offerings, Peptides International also provides custom synthesis services to meet structural requirements of specific enzyme or disease targets. Peptides International has a wealth of chemical expertise and know-how especially applicable to the design and synthesis of complex enzyme inhibitors and substrates. These include cyclic compounds (BQ-123), complex mimetics (BQ-788), peptide aldehydes (Ac-LLN), hydroxamic acid derivatives (TAPIs), alkylating moieties and others.

P.O. Box 24658Louisville, KY 40224 USA

Phone: 502-266-8787Fax: 502-267-1329

A Newsletter from Peptides International Volume 23, No. 1, 2010

Peptides International, Inc. 1-800-777-4779 E-mail: peptides@pepnet.com

Enzymes Gone Wild! Inhibitors to the Rescue!Enzyme inhibitors continue to generate strong research interest...

Product Quality and Value • Strict Confidentiality • Proactive Project Management • Friendly Service

Enzyme inhibitors and related productsPeptides International has long had a strong product focus in the area of enzyme inhibitors that includes both syn-thetic and microbial-derived materials. These include, for example, popular matrix metalloprotease inhibitors (TAPI-0, TAPI-1, TAPI-2), ubenimex, and actinonin. In addition, we also offer other key products, such as chymostatin, elastati-nal, leupeptin and epoxomicin, through our long-standing distribution relationship with the Peptide Institute of Osaka. These are available in multiple vials or in bulk quantities that offer considerable savings.

Enzymes are essential in almost all biological processes and aberration of enzyme activity is implicated in many disease states. Therefore modulation of enzyme function represents a well-researched route for drug development, a point underscored by the fact that enzyme inhibitors represent almost half the drugs in clinical use today. Design, development and study of enzyme inhibitors continue to be a major focus of pharmaceutical research. Therefore, this issue of PEPNET highlights this important area of research and includes key articles devoted to proteasome and MMP inhibitors. We hope you will find our comprehensive collection of reagents for enzyme research and custom synthesis services valuable for your innovations in this area.

Custom Synthesis ServicesPeptide aldehydes, ketones, hydroxy-isosteres•

Cyclic compounds: termini / side chain / disulfide•

Biotin, aminohexanoic acid, defined length PEGylations•

Custom designed FRET substrates and libraries•

Dabcyl, Dabsyl, Dansyl, EDANS, Farnesyl•

Coumarin derivatives, Rhodamines, TAMRA•

Glycosylated, Phosphorylated, Sulfated (Ser, Thr, Tyr)•

Isotopically-labeled derivatives: • 13C, 15N

Peptide International specializes in providing: Exploratory compound sets and libraries•

• Multi-gram to pilot-scale preparations for development and diagnostics

Please contact our technical experts to discuss your specific needs and to learn about our cost effective and value added services.

A comprehensive list of Peptides International enzyme inhibitors (“The Enzyme Inhibitor Guide”), complementary substrates (“The Enzyme Substrate Guide”) and related literature are available from www.pepnet.com or by contacting us via email peptides@pepnet.com or by phone 800-777-4779.

Crystal structure of TACE (TNF-a Converting Enzyme) in complex with inhibitor TAPI-2 (TNF-a Protease Inhibitor-2). TAPIs are proprietary TACE inhibitors sold by Peptides International under license from US Patents: 5,387,610; 5,616,605; 5686,422.Source: http://www.ebi.ac.uk/pdbe-srv/view/images/entry/2ddf600.png by J. Swaminathan & MSD staff at the European Bioinformatics Institute http://www.ebi.ac.uk/

Employee SpotlightWith over 12 years experience in commercial peptides, DeAnna Long currently serves as PI’s Director of Sales and Marketing. Dr. Long completed her Ph.D. in organic/peptide chemistry at the University of Louisville under the

mentorship of the late Arno F. Spatola, founder of Peptides International. She served as the Principal Investigator on Peptides International’s Phase I and II SBIR CLEAR-OX development grant for the synthesis of bioactive peptides. DeAnna was elected by her peers to serve on the American Peptide Society Council and currently chairs the web site committee. DeAnna and her family volunteer their time supporting the Juvenile Diabetes Research Foundation (JDRF) in honor of DeAnna's daughter. Outside of PI and schoolwork, she and her family enjoy watch-ing and playing basketball, riding bikes, and cooking. If you can teach a child to cook then chemistry is right around the corner!DeAnna credits her role at PI for giving her the opportunity to meet some of the most incredible people, our customers! After all, peptide science has led to numerous important discoveries and contributes to

the improvement of health and quality of life for many, especially all the type I diabetic children who live each day thanks to insulin therapies. While numerous challenges remain, DeAnna is inspired each day to use her job at PI to help her colleagues and friends around the world cure diseases!

Peptides International, Inc. P.O. Box 24658Louisville, KY 40224 USA

Phone: 502-266-8787Fax: 502-267-1329

1-800-777-4779E-mail: peptides@pepnet.com

Matrix Metalloproteinases (MMPs) are responsible for turn-over of extracellular matrix (ECM) components by degradation. These enzymes were first discovered in tissue remodeling that occurs during tail removal for the developmental stage of the tadpole.1 MMPs have been discovered to act on a wide number of substrates and affect a diverse number of cell functions. They act on secreted molecules, matrix molecules, and membrane-anchored proteins that include tumor necrosis factor-α (TNF-α). Downstream functional targets include wound healing, bone reabsorption and developmental processes.2 MMPs can also be a detrimental contributor to the pathogenesis of cancer, arthritis and cardiovascular and neurological disorders. Inhibitors have been designed to mimic substrates, with a zinc-ligand group such as thiol or hydroxamic acid that allows them to bind and block the catalytic site. For example, GalardinTM (INH-3927-PI) is a broad-spectrum hydroxamate MMP inhibitor which was found to significantly block tumor growth and metastasis.3 MMPs contribute to these activities by increasing growth factor activity and remodeling, conditions that favor tumor cells. MMP inhibitors have also been used to target inflammatory-related diseases. TNF-α production and activity has been correlated with inflammatory-related diseases such as arthritis, Crohn’s Disease, MS and atherosclerosis to name a few. This molecule is processed to a soluble cytokine by metalloprotease enzyme known as TNF-α Converting Enzyme (TACE). TNF-α proteinase inhibitors - or TAPIs - (INH-3850-PI, INH-3852-PI, INH 3855-PI) are known TACE or MMP inhibitors that block TNF-α processing.4

MMP Inhibitors - Tools for Drug Discovery

Peptides International is proud of the diversity of its employees, while sharing a common desire to offer our customers their absolute best in creating service and product value. This issue we would like you to meet someone who wears many hats, all of them well.

TAPIs have since been found to act on shedding of other molecules through MMP inhibition. For example, TAPI-2 has been shown to block processing of a receptor required for malignant, glioma tumor cell invasion.5

MMP inhibitors continue to be a popular choice for PI customers in their quest for greater understanding of the role of diverse MMPs in cellular signaling, function, and disease.

CODE PRODUCT QTY USDINH-3927-PI GalardinTM 5 mg 175

INH-3850-PI TAPI-O HONHCOCH2CH(CH2CH(CH3)2)-CO-Nal-Ala-NH2

1 mg5 mg

125495

INH-3855-PI TAPI-1 HONHCOCH2CH(CH2CH(CH3)2)-CO-Nal-Ala-NHCH2CH2NH2

1 mg5 mg

125495

INH-3852-PI TAPI-2 HONHCOCH2CH(CH2CH(CH3)2)-CO-t-Butyl-Gly-Ala-NHCH2CH2NH2

1 mg5 mg

125495

TAPIs are proprietary TACE inhibitors sold by Peptides International under license from US Patents: 5,387,610; 5,616,605; 5686,422.To see the many other inhibitors that are available, please visit PEPNET.COM.

1. J. Gross, C.M. Lapierre, Proc. Natl. Acad. Sci. USA, 4, 1014 (1962).2. C. Chang and Z. Werb, Trends Cell. Biol., 11, S37 (2001).3. K. Almholt, et al., Mol. Cancer Ther., 7, 2758 (2008).4. P.D. Crowe, et al., J. Exp. Med.,181, 1205 (1995).5. K. Wang, et al., PLoS Biol., 6, e289 (2008).

OHNH

NH

NH

NH2

O

O

O

O

INH-3850-PI TAPI-0

PEPNET.COM → Product Brochures → MMP Substrates and InhibitorsPlease inquire for bulk pricing, additional sizes and products available.

Dr. DeAnna W. Long

epoxomicin (IEP-4381-v) are widely used research tools to determine functional roles of UPP. Inhibition of UPP can also have many beneficial effects, including treatment of diseases. Inhibitors can disrupt protein regulation and stimulate apoptosis of malignant cells.6 The diverse application of these inhibitors was not initially recognized. They may also have a beneficial role for treatment of encephalomy-elitis, asthma, stroke therapy, and breakdown of protein in muscles.7-10 Peptides International continues to offer a variety of proteasome inhibitors and substrates for researchers.

CODE PRODUCT QTY USDIZL-3175-v Z-Leu-Leu-Leu-H (aldehyde) [MG 132]

Inhibitor for Proteasome5 mg

vial43

IEP-4381-v EpoxomicinInhibitor for Proteasome

0.2 mg vial

219

MLG-3179-v Z-Leu-Leu-Glu-MCASubstrate for Proteasome

5 mgvial

65

To see the many other inhibitors & subtrates that are available, please visit PEPNET.COM.

1. S.H. Lecker, et al., J. Am. Soc. Nephrol., 17, 1807 (2006). 2. S.W. Lee, et al., J. Am. Soc. Nephrol., 15, 1537 (2004).3. J.N. Keller, et al., J. Neurochem., 75, 436 (2000).4. S. Jentsch, Annu. Rev. Genet., 26, 179 (1992).5. A.L. Goldberg, Nature, 426, 895 (2003).6. Y. Kudo, et al., Clin. Cancer Res., 6, 916 (2000).7. P.J. Elliott, et al., J. Allergy Clin. Immunol., 104, 294 (1999).8. C.L. Vanderlugt, et al., J. Autoimmunol., 14, 205 (2000).9. L. Zhang, et al., Stroke, 32, 2926 (2001).10. S.C. Hobler, Am. J. Physiol. Regul. Integr. Comp. Physiol., 274, R30 (1998).

We appreciate the many responses to the RGD

Technology Platform, featured in the last issue of PEPNET.

To receive the RGD Technology Platform mailing and/or to be informed of further

developments in this research, please contact

us. The RGD Technology Platform brochure, PEPNET

newsletter, and our extensive RGD product sheet, are also available via PEPNET.COM. Stay tuned for further announcements about other Peptides International technology platforms in coming issues.

Step Up to the Platform!

T e c h n o l o g y P l a t f o r m

RGDComplex Organic

Derivatives

MultimersConjugates

Industry Leading Catalog Portfolio

Defined-Length PEGylations

Process Scale-up Multi-gram Synthesis

Peptides International, Inc. P.O. Box 24658Louisville, KY 40224 USA

Phone: 502-266-8787Fax: 502-267-1329

1-800-777-4779E-mail: peptides@pepnet.com

Congratulations to Jianting Wang who was recently awarded the Arno F. Spatola Graduate Research Fellow-ship by the Faculty of the Institute for Molecular Diversity & Drug Design (IMD3) at the University of Louisville. Jianting Wang is a Ph. D. student and mem-ber of Dr. Kyung A. Kang's group at the University of Louisville J.B. Speed School of Engineering. Her work focuses on highly specific and sensi-tive nano-fluorescing agents for early and accurate breast cancer diagnosis.The Fellowship was established by Dr. Spatola’s many friends and colleagues to honor his commitment to students and scientific research. For contribution information, please contact Dr. James Wittliff or Dr. K. Grant Taylor, Co-Directors of IMD3 at http://louisville.edu/imd3.

Arno F. Spatola Graduate Research Fellowship Awarded

Jianting Wang, with Jackie Spatola of Peptides International

Proteasome Inhibitors: Multiple Pathways to ResearchThe ubiquitin proteasome pathway (UPP) is a highly con- served mechanism responsible for tagging and destroying proteins. This destruction model is used to regulate apoptosis, transcription and cell signaling, as well as to participate in quality control of misfolded or damaged proteins. But as with any process, it can be detrimental in certain circum-stances.1 For example, muscle atrophy triggered during kidney disease and other catabolic states, has been shown to require

UPP activation.2 In addition, impairment of UPP can contribute to diseases such as Alzheimer’s.3 The UPP mechanism is a 2-fold, ATP-dependent process that involves activation, transport and transfer of ubiquitin to the targeted protein substrate.1,4 The tagged protein is transferred to the core of the 26S proteasome complex for degradation. The active sites in the core have a unique mechanism of cleavage where peptide bonds are severed by the hydroxyl group on a critical threonine residue.5 Due to the novel nature of the proteolytic cleavage, highly specific inhibitors for these active sites have been produced by microorganisms or chemically synthesized. Inhibitors such as MG132 (IZL-3175-v), MG115 (IAT-3170-v), lactacystin (ILC-4368-v) and

PEPNET.COM → What's New → RGD Technology Platform

PEPNET.COM → Product Brochures → Proteasome InhibitorsPlease inquire for bulk pricing, additional sizes and products available.

PRESORTEDSTANDARD U.S. Postage

PAIDPEPTIDES

INTERNATIONALP.O. Box 24658Louisville, KY 40224USA

Address Service Requested

PEPNET.COM → Product Brochures → New Products 2009PRODUCT CODE

Biologically Active Peptides

• H-Gly-Asp-Gly-Val-d-Ile-Thr-Arg-Ile-Arg-OH GDGViTRIR

PCI-3964-PI

• Mu-Conotoxin SIIIA (0.5 mg vial) PCN-4440-v

RGD Peptides

• H-Gly-Gly-Gly-Gly-Arg-Gly-Asp-Ser-Pro-OH GGGGRGDSP

PCI-3965-PI

• cyclo [Arg-Gly-Asp-d-Phe-Lys(PEG-COCH2CH2SH)] PCI-3977-PI

Carbohydrates and Conjugates

• Phenyltrifluoroacetimidate Glycosyl Donor CAR-22102

• Fmoc-Ser[Ac4Gal-Beta-(1- >3)Ac2GalNAc-Alpha- (1- >O)]-OH

CAR-22103

• Fmoc-Thr[Ac4Gal-Beta-(1- >3)Ac2GalNAc-Alpha- (1- >O)]-OH

CAR-22104

• 2- NBDLG (0.5 mg vial) Control Substrate for 2-NBDG

CKG-23003-v

Antigenic / Immunologic / EAE Peptides

• Myelin PLP (180-199) WTTCQSIAFPSKTSASIGSL PLP-3966-PI

• Myelin PLP (178-191) NTWTTCQSIAFPSK PLP-3967-PI

• Viral Protein 2 (70-86) WTTSQEAFSHIRIPLPH PVP-3971-PI

• Myelin Basic Protein (87-99) VHFFKNIVTPRTP PMB-3973-PI

NEW Products of Interest from Peptides International:

In This Issue

http://www.pepnet.com/ShoppingUsers/PdfDocument.aspx?FileName=NewProducts2009.pdf

Order soon and don't miss out! Again this year we're including a Kentucky Derby commemorative glass with qualifying orders. These glasses are highly collectable and will be shipped free by request for any order over $500. While quantities last during racing season. Limit one per laboratory, please.

It's a Tradition: The 2010 Derby Glass

Enzymes Gone Wild!• Custom Peptide Services• TAPI MMP Inhibitors• Proteasome Inhibitors• Employee Spotlight• Spatola Fellowship Winner• RGD Technology Platform Update•

Process Scale-up Multi-gram Synthesis

PEPCITE recently logged an impressive milestone: over 1200 (and counting!) unique references that cite Peptides

International. PEPCITE compiles literature, publications, and patents from leading researchers in the fields of drug discovery, drug delivery, and diagnostics that have cited Peptides International as their source. For a complete list of citations referencing Peptides International in these areas, please contact us or refer to our website PEPNET.COM.

TM

BIG Numbers

PEPNET.COM → What's New → PEPCITE

Sust

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Prin

ting

This issue of PEPNET highlights enzyme inhibitor's role in pharma-ceutical research. We hope you enjoy perusing this PEPNET edition. We look forward to hearing from you!

Coming Soon! Fluorescence Resonance Energy Transfer (FRET) Substrates Libraries, Novel Building Blocks for Drug Design, Proteinase-Activated Receptor (PAR) Peptide Agonists & Antagonists and more….