BeCellBar, LLC., STARTUP from Nagoya University.
The only company either TIGHTEN or LOOSEN
your body barriers.

Hidekazu Hiroaki, Ph.D. Professor at NAGOYA University,Graduate School of Pharmaceutical Sciences

Founder, CKO, BeCellBar LLC.

Skin Barrier
Intestinal Barrier
Airway Barrier
Blood Brain Barrier

Tight Junctions＝ epithelial barrier complex

CLDN2

EM image of TJ strand, from Prof Furuse atOkazaki Institute.

Our science: deep understanding to tight junction
Tight Junction Dynamic Equilibrium
ZO-1 inhibitors

LNX1 inhibitors

ZO1
PDZ1CLDs✖

C

LNX1
PDZ2

ZO1PDZ1
LNX1
PDZ2

TJ may open
NPL-3004, 3013
Flavonoid baicalin, quercetin
NSAIDs

ZO1
PDZ1✖

LNX1
PDZ2

TJ may over-integrate and close
NPL-1011, 3009
Flavonoid X

Our Science :We already found the both types of COMPOUNDS,
tight junction openers (left) and tight junction enhancers (right).
ZO-1 inhibitors

Cell 1

Cell 2Tight junction

LNX1 inhibitors

Cell 1

Cell 2Tight junctionOur science :We used “structure-guided drug design” and “NMR-screening” methods
to efficiently explore TJ-opening and TJ-enhancing compounds.

ZO1-PDZ1(2RRM)

LNX1-PDZ2(3VGF)

LNX1-PDZ2 / JAM4(3VQG)

1. Ready to use for in silico inhibitor discovery
2. Secondary screening by ultrasensitive 900MHz NMR technique.

Strategy : “barrier function enhancers”
Fruit derived
flavonoid
naringenin
hesperidin

Original compounds
NPL-1011
NPL-3009

TJ enhancement

Supported by AMEDtranslational research
grant (2020)

TJ
Epithelial cells

pathogenssoluteswaterStrategy : “barrier opener” as “absorption enhancer”
Plant derived
flavonoidbaicalinquercetin

anti-CLD2

Original compoundsNPL-3004
NPL-3013

anti-CLD2

TJ reduction

TJ
Epithelial cells

pathogenssoluteswaterOur compounds :Small mol-wt 1011 (TJ enhancer) / 3013 (TJ opener)
Control (DMSO)

NPL-1011

TJenhancer
anti-CLD2

anti-CLD2※DMSO final conc. 0.1％, same developmental time, scale 50 µm

FITC-dextran
NPL-3013

TJopeneranti-CLD2

anti-CLD2

TJ enhancer and TJ opener are bounders to LNX1-PDZ2
and ZO1-PDZ1, respectively.

permeation assay
FITC fluorescenceControl (DMSO)

15000
10000
500000.1% DMSO

100 µM

100 µM

30043013

Targets and their markets
LEAKY GUT SYNDROME, that may include1.

non-celiac gluten sensitivity, NCGS

2.

irritable bowel syndrome, IBS-D

PLAN A: provide prophylactics and supplements for wheat-sensitive
patients and IBS-D patients by plant derived flavonoids.
We will create a new market for alternatives of gluten-free foods andlow-FODMAP foods.
PLAN B: meanwhile, start to develop NPL-compounds as pharmaceutics.
In both cases, food ingredients cause inflammation and immunedisorders. Enhancing intestinal barrier function can block thesymptoms.

Problems to be solved
1.
non-celiac gluten sensitivity, NCGS
Provide methods (treatments, prophylactics, supplements) to prevent or
alleviate non-celiac gluten sensitivity symptoms especially for patientscomplaining of NCGS .
Especially in case of difficult to obtain gluten-free diet.

2.
irritable bowel syndrome, IBS-D / leaky-gut syndrome
Provide methods (treatments, prophylactics, supplements) to prevent or
alleviate symptoms of the diarrhea type of irritable bowel syndrome (IBS-D)and leaky gut syndrome.
Many patients of leaky gut syndrome who are not gluten-dependent, areespecially sensitive to certain FODMAP components. We provide alternative
method other than FODMAP-reducing diets.
In both cases, food ingredients cause inflammation and immune
disorders.

Non-celiac gluten sensitivity, NCGS
NCGS: (definition and characteristics)
1. A clinical entity induced by the ingestion of gluten leading to intestinal
and/or extraintestinal symptoms that improve once the glutencontaining foodstuff is removed from the diet.
2. Celiac disease and wheat allergy have been excluded.
3. Diagnostic molecular marker for NCGS has not yet been established.
4. Certain part of patients are overlapping with those of diarrhea typeirrigatable bowel syndrome, IBS-D.
5. The population of NCGS patients in US is approximately 20 million.

Market size = $4.3 billion (2019) (gluten free food)
Certain part of this market can be replaced by our products.
Our strategy = to use general purpose barrier enhancer ingredientwith high quality scientific proof of concept.
2

Targets and their markets
Barrier opener as absorption enhancer
1.

Cosmetics, with several growth hormones and growth factors

2.

Peptide vaccines for transdermal administration

3.

Oral administration of insulin and GLP

Development of clinically usable absorption enhancers will take a long
period (4 – 7 years), whereas application to cosmetics can be achieved
within a year (we already have an offer from a domestic cosmeticcompany.)FUTURE PLAN
We are now developing bi-directional tight junction
open & close technology.
Combined use of 2 (open) and 1 (close) as an ideal
DRUG ABSORPTION ENHANCERS.
1. OPEN

2. ENTER3. CLOSE

Our teamCEO:

Takeshi Tenno, PhD (Science)

Graduate School of Science and Engineering, Ehime University.
Designated Associate Professor, Kobe University
Designated Assistant Professor, Nagoya University
Current
Visiting Scientist, Graduate School of Pharmaceutical Sciences, Nagoya
University.

Field of expertise: Protein Science, Cell Biology
CKO:

Hidekazu Hiroaki, PhD (Pharmaceutical Sciences),pharmacist

Graduate School of Pharmaceutical Sciences, Osaka University.
Nippon Roche Research Center
F Hoffman La Roche (Basel)
Biomolecular Engineering Research Institute, CO. Ltd.
Associate Professor, Yokohama City University
Designated Professor, Kobe University
Professor, Graduate School of Pharmaceutical Sciences,
Nagoya University.

Field of expertise: Structural Biology, Biophysics
050602YCU

Thank you for your patience!
BeCellBar, LLC.

Supporting information

補足資料

2016年頃まで主流だったセリアック病/NCGSの発症機構

補足資料

2016年頃まで主流だったセリアック病/NCGSの発症機構仮説のこの部分はまだ否定されていない

Zonulin分子のEGF様活性そのものが否定されつつある
市販Zonulin抗体の品質が悪くNCGSの診断指標になりうるとした論文が否定された仮説のこの部分はまだ残っている（堅牢）What we found ?
1. Tight junction (TJ) is dynamically regulated between

biogenesis and down-regulation (internalization /degradation) by two proteins.
2. TJ biogenesis is promoted by ZO-1.
3. TJ down-regulation is promoted by a ubiquitin ligase, LNX1.
Collaborator, Prof. Furuse (NIPS, Okazaki)

Our compounds :Small mol-wt 1011 (TJ enhancer) / 3013 (TJ opener)
Control (DMSO)

NPL-1011

TJ
enhanceranti-CLD2

anti-CLD2※DMSO final conc. 0.1％, same developmental time, scale 50 µm

FITC-dextran
NPL-3013

TJ
openeranti-CLD2

anti-CLD2

TJ enhancer and TJ opener are bounders to LNX1-PDZ2
and ZO1-PDZ1, respectively.

permeation assay
FITC fluorescenceControl (DMSO)

15000100005000
00.1% DMSO

100 µM

100 µM

30043013

Problems to be solved
1.
non-celiac gluten sensitivity, NCGS
Provide methods (treatments, prophylactics, supplements) to prevent or
alleviate non-celiac gluten sensitivity symptoms especially for patientscomplaining of NCGS .
Especially in case of difficult to obtain gluten-free diet.

2.
irritable bowel syndrome, IBS-D / leaky-gut syndrome
Provide methods (treatments, prophylactics, supplements) to prevent or
alleviate symptoms of the diarrhea type of irritable bowel syndrome (IBS-D)and leaky gut syndrome.
Many patients of leaky gut syndrome who are not gluten-dependent, areespecially sensitive to certain FODMAP components. We provide alternative
method other than FODMAP-reducing diets.
In both cases, food ingredients cause inflammation and immune
disorders.

Non-celiac gluten sensitivity, NCGS
NCGS: (definition and characteristics)
1. A clinical entity induced by the ingestion of gluten leading to intestinal
and/or extraintestinal symptoms that improve once the glutencontaining foodstuff is removed from the diet.
2. Celiac disease and wheat allergy have been excluded.
3. Diagnostic molecular marker for NCGS has not yet been established.
4. Certain part of patients are overlapping with those of diarrhea typeirrigatable bowel syndrome, IBS-D.
5. The population of NCGS patients in US is approximately 20 million.

Market size = $4.3 billion (2019) (gluten free food)
Certain part of this market can be replaced by our products.
Our strategy = to use general purpose barrier enhancer ingredientwith high quality scientific proof of concept.
2Strategy for growth
1.

Synthetic tight junction modulators

Pharmacological effect is stronger than the others.
Specificity may be high.
Long term and high costs for approval.
Market is thought to be large.
-> Application for medicines“transdermal / trans-nasal administration for peptide vaccines(for COVID19)”
2.

Plant-derived tight junction modulators

Effect is moderate.
Safety concerns and risks are low.
-> Cosmetics, food supplements

Thank you for your patience!
BeCellBar, LLC.

Recent publication (2020)
Eur J Pharmacol
High dose of baicalin or baicalein can reduce tight junction integrityby partly targeting the first PDZ domain of zonula occludens-1 (ZO-1)