HiPep-O-001E Company Brochure 20240511A4Eng©HiPep Laboratories 2024

Research and Development

Supported by HiPep® Technologies
Most of amino acid molecules are consisting of D and L enantiomers (mirror image) such as a right and a left hand. Biologicalactions often depend on the conformation of molecules. HiPep Laboratories has the potential to open the door of those mirror
and to reveal molecular recognition. Thus, we are going to develop applications of those molecules. (Logo mark)

HiPep® Technology
High Throughput + High Quality + Highly Efficient Synthesis and Characterization of Peptides and their
Related Materials

PepTenChip®
A sensor device, discriminates protein-structures, not only 1:1 recognition. Proteins can be mimicked by peptides.
Designed Peptide Arrays have numerous advantages and high-quality industrial production are promised. Unlike proteins
peptides as capture molecules can be used even after dried. Due to the original technologies, PepTenChip® can be
repeatedly used, realization of SDGs, Sustainable Development Goals.

HiPep Laboratories was founded focusing on development of novel bio-detection systems, exploration andclinical applications of biologically active peptides and their derivatives such as synthetic vaccines, biomimetic
materials, etc. HiPep provides consulting services for biomedical research, contract-based research involves
syntheses, analyses, characterization. Additionally HiPep Laboratories performs production and sales of
instruments, laboratory equipment, and reagents useful for construction of combinatorial chemical libraries.
The core technology designated “HiPep®” is syntheses, characterization, and purification of peptides and theirderivatives in a highly efficient manner. HiPep Laboratories has been focusing on molecular recognition in thecontext of peptides/proteins and their conformations/functions. The major R & D targets is production of biochip with the novel & original concepts.
Dr. Kiyoshi Nokihara
Founder & CEO/CSO, HiPep Laboratories
Corporate Philosophy
HiPep Laboratories was founded in 2002 fordevelopment of novel biochips with designed
peptide arrays, research and clinical application ofnovel active peptide, application of peptide tobiomaterial and development of drugs. Parallel
performing own R and D, consultations andcontract basis R and D. Additionally we provide
compoundlibrary
andrelateddevices/
instruments & reagents.
Through our research and development inbiomedical science, we would like to contribute to
early
detection,
prevention
andeffective
treatment of diseases which will help QOL
improvement, including development of humanresources. By taking advantages of founder’scareer and proficiency, we are proceeding
interdisciplinary
researchandbusinesscollaboration and expanding world wide.

（株）ハイペップ研究所
https://hipep.com

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HiPep-O-001E Company Brochure 20240511A4Eng
Biographical Sketch of Kiyoshi NOKIHARA(Doctor of Pharmaceutical Sciences)©HiPep Laboratories 2024

HiPep Laboratories Contributes to Society Growing to
be a Leading Company for Bio-Medical Research

The CEO and CSO of the HiPep Laboratories, Dr. Nokihara, initially studied Organic Chemistry and Chemical Engineeringin Tokyo, followed by many years of academic research in Germany. His involvement with bio-molecules commenced at
Deutsches Wollforschungs Institute at the Technischen Hochschule Aachen (1973-1979). In 1980-1985, he was
Assistant Professor of the Faculty of Pharmaceutical Sciences, Shizuoka Prefectural University, where he undertook
extensive research on brain-gastrointestinal peptides, syntheses as well as immunochemical and endocrinology studies.
He subsequently relocated to the Faculty of Medicine, University of Heidelberg in the role of visiting Professor, and laterat the GBF (German Research Centre for Biotechnology). In 1990 he joined the Shimadzu Corporation, as a General
Manager in R & D of the Biotechnology Instruments Department and Head of the Life Science Center. He has developed
several novel instruments focusing on applications, including the simultaneous multiple automated peptide synthesizers,
for which his team received a prize bestowed by the Japanese Agency of Science and Technology. His expertise was
focused on the biochemical and medical fields, especially proteins and peptides, from isolation, synthesis andcharacterization to biochemical and medical applications. As well as his business commitments he received visiting
Professor positions at the Tokyo University of Agriculture and Technology and the Tokyo Metropolitan Institute for
Neuroscience Research to continue his academic research. In 1997 he founded Shimadzu Scientific Research Inc. and established a novel researchbusiness as the Chief Scientist. In 2002 he has independently founded a new venture company, the HiPep Laboratories, based on his knowledge
and experiences in bioscience. Since 2002 he is a visiting Professor in Nanjing Medical University (China). In 2017 he was invited as a first foreign
Professor at the School of 1st Clinical Medicine of Nanjing Medical University in addition to visiting Prof. of Faculty. Since 2019 he was invited
additional the vising Professor position in Kangda Medical College, Lenyung Gan, China. He has around 300 publications and 130 patent applications.

Current Business
Applications of on biological functions and molecular recognitions based on peptides and proteins
Construction of peptide libraries, related devices, reagents and consumers: Major commercial products were developedfor in-house use (own research)
Application oriented consultation, contract research, and training
Contract production for peptides and bioconjugates and characterization, discovery, structural optimization by design
Amino acid analysis, chiral analysis, detection of contaminants, MS analyses for proteins and peptides

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HiPep® Technology

Major Technologies andProducts from Recent Research
Based on academic research in an interdisciplinary field as well as business experiences, HiPep Laboratories was founded in 2002 focusing on thebiomedical applications of molecular recognition, which is one of the most important issues in the homeostasis of a living organism, fordiagnostics and theranostics. Recently development of peptides-microarray systems for protein detection has been completed. Additionally a
production system for polyamides consisting of pyrrole and imidazole residues which recognize double-stranded DNA has been also studied bywhich gene-related therapies and novel probes were developed.

Major products were developed originally for in-house use
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Applications of biological functions based on peptides/proteins
Design and construction of compound libraries, related devices & reagents, and consumers, which are originally for in-house use
Novel separation columns with high resolution (HiPep-HPLC Columns)
Consultation, Contract research, Contract characterization (Analyses), Training : based on good facility with expertise
Designed compound libraries, on beads immobilized peptides
PepTenChip®, novel bio-detection system for Protein detection/Profiling, Novel materials made from amorphous carbon for bio-chips,
micro-reactors and micro-analyzers.

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PepTenChip®

HiPep-O-001E Company Brochure 20240511A4Eng©HiPep Laboratories 2024

Protein-protein interaction mimicked by peptides: Biodetection, Diagnostics

Based on the principle that proteins can be mimicked by de novo-designed peptides, we are focusing on two major researchareas; one is the novel bio-detection technology for diagnostics and another is development of functional molecules fortheranostics. Characterization of proteins by high-throughput technologies are in great demand. During the last decadeconsiderable effort has been devoted to the development of a novel bio-detection system using structured peptides withfluorescent dye as labels for capture molecules. These peptides are arrayed on the surface of novel chip material, amorphous
carbon, with the novel surface chemistry. The novel concept and key technologies for bio-detection have been established[Reviewed: Solid-Phase Synthesis and Combinatorial Chemical Libraries 2004, ed. Epton, R. pp 836, 2004]. The microarraysystem allowed minimization of amounts of both analytes (nano gram) and capture molecules (several femto moles).Designed
peptides have been used as capture molecules in our bio-detection [FEBS Letters, 586, 325, 2012, ibid. 587, 673, 2013]. "Thestructural changes of the protein as an analyte are reflected in the florescence intensity changes of peptides as capture
molecules in a dose dependent manner. The changes can be visualized as a pattern in a color bar-code which is designated a“Protein Fingerprint” [Chemistry and Biology, 10, 53, 2003; Molecular BioSystems, 2, 113, 2006, Patents of EU, Japan andUSA; Bull. Chem. Soc. Jpn., 83, 799, 2010]. In contrast to a conventional detection method, using a set of “antigen-antibodies”,
our detection system does not involve the detection of specific molecules themselves (so called “biomarkers”) in a 1:1 manner,
but the principle of detection is the differences in fluorescence intensity change caused by the analytes derived from normal vs.
diseased subjects, for example. Recently the novel concept and key technologies for bio-detection have been completed.

➢PepTenChip®, a sensor device,discriminates protein-structures.
➢PepTenChip® is not only 1:1
recognition.
➢Not disposable, repeatedly
used
Advantages of amorphous carbon① Mechanically stable② Chemically inert③ No self-fluorescence④ Easily manufactured⑤ Environmentally friendly (easierregeneration) , allowed to re-use.
⑥ Higher thermal & electroconductivity (allowing ionization)⑦ Extremely low back ground

PepTenChip®

Excellent Surface Technologies• Lower non-specific protein

Peptide Design & Library
Construction → HighDensity Peptide Arrays

absorption• Uniformed distribution of functionalgroups• Uniformed spot-formation on chips• Easy handling• Functional group-rich surface(easier immobilization)• QC-methods for quantization of
surface is established (PAT)

Detection:
Pattern
Recognition

Protein Fingerprint Method
Data Mining: Statistical Methods

Deposit Immobilization

Euclidean distancematrices; Clustering
dendrograms; PCA

Novel Material
Amorphous Carbon

Detector, PepTenCam (PAT),
adaptable to PFP with easy
handling, maintenance free,Low cost, portable, can beused in biosafety level 3 & 4
laboratories.

PepTenChip® is: powerful diagnostic tools/examination, diagnostics, prognostics and health management; provide the objective
indicator not depending on doctor's skill, i.e. oral healthcare, neuronal diseases such as multiple sclerosis and early detection of precancer status. allows avoiding to visit clinics/hospitals, because of examination requires long waiting time, accompanies with pain
etc. Not compete conventional diagnostics, used by clinicians without hesitation because of the revenue.
Recent R&D: While PepTenChip® allows rapid differentiation of diseases to enable an objective evaluation by clinicians, on-goingtargets are neuronal diseases such as multiple sucraloses of which cause is unknown. Atrophic gastritis is considered as an earlystage of cancer and the risk in the carcinogenic rate is higher. Instead of pathological observations, rapid and simple differentiation
method is desired. PepTenChip® system with multivariate analyses are underway. Additionally the chip can directly be inserted into
MALDI-TOF-MS after fluorescent detection and discovery of undefined materials caused diseases and/or surrogate markers can be
possible. Since the system allows noninvasive diagnostics and on-site Point-Of-Care, the PepTenChip® has potential for applicationin diagnosis of incapacitated patients. Real time and on-site manner serve AI-assisted remote diagnostics and home care. Not
compete conventional diagnostics, used by clinicians without hesitation because of the revenue.
Microarray printing services: Utilizing the most advanced microarray manufacturing facilities (Class 100 clean room) andexpertise using patented concepts and novel substrate made from amorphous carbon. Detection service is also available.
®

Alliance and Collaboration®

HiPep (Core Technologies), PetiSyzer （Personal Synthesizers）®
®
LibraTube （Multi purpose vessel）, PepTenChip （Biodetection tool)

Peptide derivatives & Construction of Library; High-through put screening, Drug discovery; DDS-design = Peptide Vehicle;
Bio-detection tools (Peptide Microarray) ★ Devices, Reagents and HPLC-columns developed for in- house use.
★ Contract syntheses analyses and consultation

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HiPep-O-001E Company Brochure 20240511A4Eng©HiPep Laboratories 2024

Bio-conjugates & Drug-discovery:
Recognition of Proteins and DNAs
Discovery & Cell Therapy (DDS) Bioconjugate: Peptide-Vehicle

PIPA-drugs as Gene Silencer: Novel therapeutic agents
PIPAs, peptides consisting of non-proteinogenic amino acids, Nmethyl-pyrrole and N-methyl-imidazole as major building blocks.
PIPAs bind to specific nucleotide sequences in the minor groove of
double helical DNA with high affinity and specificity [P. B. Dervan
et. al., Nature, 391, 468, 1998].

PIPAs are resistant to nucleases anddo not require any particular delivery
One cyclic peptide on One Bead
Library
supply&ServiceforDiversity 246 ca. 200 millions (Xsequence investigation available. systems. PIPA blocks binding of= 19 natural & 5 non-nat. AAs)
transcription factors and inhibiting
Novel OPOB-Library, focusing
gene transcription. Thus PIPA can beon drug-likeness and expanded
applied as novel chemical probes or
Chemical space..
vehicle for delivery that is the use forAmino Acids, 48, 2491, 2016;
diagnostics or therapeutic agents.
Chem. Biol. & Drug Design, 102, 1327, 2023;
PIPA is difficult to be synthesized,
Analytical Sciences, 2024, in press
Peptide-vehicle: Tetrahedron Lett. 55, 4091, 2014
although we have constructed a
Peptide nucleic acids (PNAs) [Pipkorn. R., et al., Int. J. Med. Sci., 9, 1,
industrial scale production system2012] and used as chemical probes for FISH.
and quality controls for PIPA have
Novel aspects and advantages of the Peptide-vehicle
been established.
1. DDS; 2. Specificities; 3. Novel Patents; 4. Selectivity to cell lines; 5.
Telomere visualization probe: http://hipep.jp/?cat=95; J. Am. Chem.
Against drug-resistance; 5. Combinatorial functional modules; 6. The
Soc. 136, 11546 (2014); Scientific Rep. 6: 29261 (2016) open accessvehicles are expected to be more effective novel drug

Regenerative Medicine: Angiogenic Peptide: AGP;
BBRC, 310, 153, 2003; BMC:
DOI:10.1016/j.bmc.2020.115685
JPRTher, 28, 1-4, 2022.
DOI 10.1007/s10989-022-10404-2.

Company Profile

Mimosine, non-proteinogenic amino acid &Mimosyl Peptides as ingredients forcosmeceuticals or pharmaceuticals A large scale
extraction, purification, physicochemical characterizationof high quality Mimosine from plant Leucaena
Oleucocephala de Wit has been established Nokihara, K,
H
et.al., Amino Acids, 54, 27-36, 2012.
O
Nokihara, K, et.al., Peptide Science 2010, p 282, 2011.

Corporate History
2002 March: Based on the successful results of the Millennium Project (MEXT,
2000-2002), HiPep Laboratories was founded by Dr. Nokihara focusing on
development of novel biodetection systems. HiPep Laboratories also provide
contract research in discovery and screening, syntheses, analyses &characterization of bio-molecules. Additionally, HiPep produces laboratory
instruments and consumers fundamentally developed in house use. The coretechnology, designated HiPep® Technology, is the founder’s life work. May: Wet
laboratories were completed in Kyoto-city. November: Memorial conference on
HiPep-opening was held and current collaborators and dealers were attended.
2004 September: Okinawa bio-project was started and a new additional
laboratory was set up in the middle part of main island. December: Bio-Venture
Project has been approved by the New Energy and Industrial Technology
Development Organization and received a grant-in-aid.
2005 February: Opening conference of HiPep-Okinawa Laboratory was held.
April: The prize in the Bio-Business Competition was bestowed. June: Laboratory
space in Kyoto has been expanded and laboratory for protein characterization
was newly opened.
2006 November: Celebration 5th anniversary of HiPep and scientific conference
was held with several invited speakers, mainly collaborators.
2007 March: Both office and laboratory spaces in Kyoto were further expanded
up to 1.4 times lager. July: A five years national project, R&D Program for New
Bio-industry Initiatives National Agriculture and Food Research Organization wasstarted with grants(Prion Project).
2008 May: The Program for Creating Okinawa Innovation was adopted by the
Gant-in-Aid for Cabinet Office, Government of Japan and Okinawa Prefecture, andlaboratories for cell biology were completed.
2009 October: The Adaptable and Seamless Technology Transfer Program
through Target-Driven R & D, Japan Science and Technology Agency, wasbestowed.
2010 A novel application of PepTenChip® has been developed which can be useddirectly as a sample plate of MALDI-TOF mass spectrometry, thus the dual mode
biodetection could be shown as a “hyphenated technologies”.

Access to HiPep Labs
from Kyoto Station (1) JRSaga-San-in-line (track33) getting off at Nijo-eki,
the 2nd stop (5 min ride).
From Nijo-eki, [a] ca. 15
min walk (north and theneast), [b] Taxi (5 min), toshow your driver “下立売通千本東入：二条北小学校”,[c] City bus, No. 201, 206,
6 or 46 get off at SenbonMarutamachi andcrossing Senbon-Dori 4
min. walk eastward.
(2) By Subway at Karasuma-Oike transfer to the Tozai-line and get off
at Nijo-Castle, 10 min walk north & Marutamachi-dori west).

O
H
O

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NH2

2011 April: Taking in account of economical influences caused by tsunami andearthquake in Tohoku, Okinawa lab was closed and all activities were focused in Kyoto.
September: A clean room for biochip manufacturing was reconstructed.
2012 The conference of 10 years anniversary-celebration of HiPep was performed andseveral invited scientific collaborators gave their excellent lectures.
2013 R&D Prize of New Technology Foundation 2013.
2014 By the aid received in 2013 all fundamental technologies concerning novel
biodetection system, PepTenChip®, consisting of libraries for captured molecules,
chip-plate (novel material made from amorphous carbon, high through-put arrayer
and fluorescent detector) have been completed. NEDO-Grant, Innovation Venture R&D
Support, was began, the theme was development of industrial production of PIPA asAPI. Hence, not only proteins but also double strand DNA-specific recognition wasproceeded.
2015 NEDO-project has been successfully terminated. Further, the system-design andimprovements for practical production were carried out and larger scale syntheses
have been performed for evaluation. The grant of Ikeda-Senshu Bank was bestowed
for Oral-Health care hence PepTenChip® system ws applied.
2016 March: HiPep-Korea (HPK) was founded for Korean life science markets. May:
HPK-Foundation Memorial Conference in Suwon Bio-Center. August: a spin off
company, PIPLS Pharma (Peptides containing Imidazole and Pyrrole as building blocksLarge scale Syntheses) was founded based on R&D results during the last decade
performed by HiPep Laboratories. PIPLS Pharma focuses on GMP production of highquality peptide derivatives, especially peptide conjugates and PIPA for clinicalapplications. PIPA is a novel drug candidates with novel action mechanisms such as
gene controls. Industrial scale GMP-products is indispensable for clinical trial as well as
FDA-approval.
2017 Two big exhibitions in March at the BioKorea, lecture was also given) and in April
Korea-Pharm. June joined in Bio2017, San Diego, ca 70 business partnering werecarried out. Two grants for Longer-Life, Kyoto-City and local collaboration project withacademia (Kyoto-prefecture) have been received: former regenerative medicine andlatter biodetection in neuronal diseases . Dec. Dr. Nokihara was invited as a firstforeign Professor at School 1st Clinical Medicine, Nanjing Medical University, China. And
a Visiting Professor in Nanjing Medical University (Faculty) is further continued.
2019 July, Grant “Project for Strategic Fundamental Technology Advancement
Support” (METI) was received, which is focusing on applications of PepTenChip®.

Trade Name
Principal Office
Contact
FoundedCapitalMain Banks
Administration
Board

HiPep Laboratories
Nakatsukasa-cho, 486-46, Kamigyo-ku, Kyoto,602-8158, Japan
E-mail info@hipep.jp URL http://www.hipep.jp
Tel: +81-75-813-2101 Fax:+81-75-801-0280
March 29, 2002
22.5 million Japanese Yen （as of April 1, 2022）
Mitsubishi-UFJ Bank, Kyoto Bank, Mizuho Bank,
Kyoto-Shinyoukinko
CEO & CSO Prof. Dr. Kiyoshi NOKIHARA
Ryosuke NOKIHARA; Dr. Toru SASAKI
Auditor: Tomoko NOKIHARA

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