Partnership with TB Alliance for anti-tuberculosis drug discovery
from natural products
November 19, 2021

Isshin Tanaka
Applied Microbiology Group
Biological Research Department

My working experience in drug discovery from natural products
Developed and commercialized
natural product-derived pravastatin asa cholesterol-lowering drug

1995–2007

Sankyo Co., Ltd.

2007–2011

Daiichi Sankyo Co., Ltd.

2011 to present

Daiichi Sankyo RD Novare Co., Ltd.

My initial task:• Curating a microorganism library

Basidiomycetes that form minute basidiocarp

My current task:• Finding an effective use of the microorganism library and microbial extract
libraries• Developing new technologies for drug discovery from natural products
2What is Daiichi Sankyo RD Novare?
Daiichi Sankyo RD Novare was established in 2011 with a mission of playing arole in the global R&D function of the Daiichi Sankyo Group by building an
advanced technological foundation that supports innovative drug discovery anda high-quality clinical development process3Microorganism library of Daiichi Sankyo RD Novare
Fungi
Discomycetes・Basidiomycetes・
真菌
Endophytes

Actinomycetes
放線菌 Actinomycetes
Rare

Bacteria
細菌bacteria
MarineCharacteristic microorganisms of each groupØ Contains a large number of strains isolated from terrestrial and marine environments
in JapanØ Organized by molecular systematics based on rDNA
Ø Utilizing the crude fermentation extracts derived from the microorganism library in ourresearchØ This library and research function were inherited by Daiichi Sankyo RD Novare fromSankyo
4

The origin of our collaboration with TB Alliance in 2014
Ø TB Alliance planned to conduct anti-tuberculosis drug discovery
research from natural products in Japan and had been surveying
Japanese research institutes through the GHIT Fund
Ø Daiichi Sankyo RD Novare was seeking a chance to expand
utilization of microorganism library

We received an explanation from the GHIT Fund and understood the significance ofcollaboration• Strong needs for Novare’s microorganism library• Supported research costs by GHIT Fund and PDPs
• Expected contribution to global health through our expertise in drug discovery
research5

Screening project started in 2015
〜1980s Former company Sankyo did drug discovery research. Since the 1980s, thecompany's research had been shifting to other areas of unmet medical needsResearch suspended over 30 years
Technology has advanced during this period

・Molecular phylogenetics
・Increased understanding of microbial genomes
・Development of synthetic biology

2015 Screening project started
Differences from screening 30 years ago• Use expanded and more diverse microorganism library organized bymolecular systematics• Use Mycobacterium tuberculosis, not Mycobacterium smegmatis, forphenotype screening
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Status of GHIT-sponsored projects with TB Alliance

Not Awarded from GHIT (2017)
Hit-to-Lead project

Screening2015〜2019Awarded from GHIT (2019)
Hit-to-Lead projectHit-to-Lead2019〜
Discovery of novel active compounds
Completed PJ

A new project started based on the achievements so far

Active PJ

Screening

2021〜
7Roles in the screening project
Refermentation

RD NovareFermentation
extracts

Preparing Fr. samples

Isolation
Structure elucidation

Fractionatedsamples

Activecompound

Phenotype screening

TB Alliance

Confirmationof activity

University of Illinois Chicago(USA)
Japan Anti-Tuberculosis Association(Japan)

Biotranex(USA)

Applying for GHIT
Hit-to-Lead projectADME
BioDuro-Sundia(China)Evotec(USA)

Research material
Research activity

Texas A＆M University(USA)8Role of Daiichi Sankyo RD Novare in the Hit-to-Lead projectØ Make the derivatization plan with TB AllianceØ Provide the parent or analog compounds used for derivatization
Ø Gram-scale compounds are neededØ Analogous compounds or basic skeletons of the compounds useful fordiversification of semi-synthesis

To provide the compounds efficiently, we wanted to utilize genomic
information and biosynthetic genes of the producing
microorganisms
9Prospects for utilization of microbial genome
Microbial genome and biosynthetic genes

1

Productivity improvement

23456

7

Generation of novel compounds
657
1

4
NutrientsNutrients

365

Natural ProductByproducts

513

Natural Product674

Byproducts

2267514327143210

Take home message
1. Microorganism libraries are still an attractive source of new drug
leads where new active compounds can be found
2. With support from GHIT Fund, this proven and limitless source canbe put to great use for neglected diseases
3. A combination of the know-how accumulated within our organizationand new approaches in microbial genomes and biosynthetic genes
can generate novel leads

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AcknowledgementsBiological Research Department
Yasunori Muramatsu
Youko Fujita
Tadaaki Morishita
Masaaki Kizuka
Takahiro Miyauchi
Yasunori Ono
Emi Kurosawa
Shinobu Abe
Tomio Ishikawa
Hanako Nishizawa
Organic & Biomolecular Chemistry Department
Marumoto Shinji
Hiroki Shimizu
Tetsunori Fujisawa
Hiroshi Maruoka
Pharmaceutical & ADMET Research Department
Yoshimine Fujii
Masaru Iwasaki

GHIT Fund
GHIT Fund Management teams
TB ALLIANCE
Dr. Takushi Kaneko
Dr. Nader Fotouhi
Zaid Tanvir<Cross-sector partnerships of TB ALLIANCE>
Japan Anti-Tuberculosis Association
Dr. Norio Doi
Dr. Yasuhiro HoritaUniversity of Illinois Chicago
Professor Scott G. Franzblau
Various other research institutes
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