vladislav deigin peptide pharmaceuticals in russia and worlwide
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Peptide Pharmaceuticals: Development in Russia and Worldwide
Vladislav Deigin
“Peptos Pharma”Moscow, Russia
Shemyakin & Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences, Moscow, Russia
JV “Pharma Bio”
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GenomicProteomic
Peptidomic
Planet Galaxy
Universe
Peptides – universal bioregulatorsPeptides – universal bioregulators
NH
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Topics for discussion:
Peptide drugs: current landscape and perspectives;
Pipeline of peptide pharmaceuticals: contribution of Russian science;
Novel approach for next generation development of peptide pharmaceuticals
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Topics for discussion:
Peptide drugs: current landscape and perspectives;
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Total amount of registered API in USA and Europe
Non-peptide/protein drugs (over 5000)
Peptide/protein drugs (~60 synthetic peptides and ~15 proteins)
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Peptide pharmaceuticals – one of the fastest growing segments of the world market
Clinical indication for the peptide drugs. Publications related to synthetic peptide preparations
Sales volume for 10 the best selling peptide pharmaceuticals Number of peptide products in the development pipeline in 2008
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Topics for discussion:
Pipeline of peptide pharmaceuticals: contribution of Russian science: - Pharmaceuticals - Peptide vaccines - Oral delivery system
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Topics for discussion:
Pipeline of peptide pharmaceuticals: contribution of Russian science: - Pharmaceuticals
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There are 13 original branded peptide drugs developed and marketed in Russia
Peptide pharmaceuticals: Route of administration1 Dalargin (anti –ulcer) - IM
2 Thymogen (immunomodulator) - IM, Intranasal
3 Semax (neuroprotector, after stroke ) – Intranasal
4 Likopid (immunomodulator) - sublingual tablets
5 Immunofan (immunomodulator) - - Sq. injections
6 Thymodepressin (immunosupressor) – IM, Intranasal
7 Deltaran ( adaptation, neuroprotector) – IM
8 Gepon – (antiviral, immunomodulator) - Sq. injections
9 Sedatin (vet. market) - (stress – and anxiety protector)
- IM, Intranasal
10 Bestim – (immunomodulator) – IM
11 Allokin-alfa - Subq. injections
12 Noopept (nootropic) – oral tablets
13 Stemokine (Neogen) – (hemopoietic booster) – IM, Intranasal
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Latest survey of research areas in modern drug discovery field
Over 53% of most active researchers are dealing with immune-related drug - candidates
Research related to immune system
Published by Bioinformatics LLC
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Peptides affecting the immune system – the most advanced area of peptide pharmaceuticals approved in Russia
Immunoactive Peptide Pharmaceuticals:
Indications
1 Thymogen Immunomodulator, antiviral
2 Likopid Immunomodulator, antiviral
3 Immunofan Immunomodulator, antiviral
4 Thymodepressin Immunosupressor
5 Gepon Immunomodulator, antiviral
6 Bestim Immunomodulator
7 Allokin -alpha Immunomodulator, antiviral
8 Stemokine (Neogen) Hemopoietic booster, Immunomodulator
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Лекарственные препараты разработанные «Пептос Фарма»
Immunomodulators Immunosupressor
Hemostimulant
Approved peptide pharmaceuticals developed by IBCH RAS and “Peptos Pharma Ltd”
Thymogen for injections Nasal Spray Thymogen for injections Nasal Spray
Stemokine for injections
Likopid tablets
Neurotropic Neurotropic
pharmaceutical pharmaceutical
for treatment of for treatment of
neurotic neurotic
and stress related and stress related
disordersdisorders
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D-GLU –D-TRP
Thymogen
L-TRPD-
D-TRP
L-GLU
D-GLU
Thymodepressin
IMMUNOSTIMULATION IMMUNOSUPPRESSION
L-GLU –L-TRP
CHEMICAL AND OPTICAL STRUCTURES OF GLU –TRP ISOMERS
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T- cell
B-cell
L-L (natural)
D-D (synthetic antagonist)
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1. CONTROL 2. CYCLOSPORIN A (50 mg/kg) 3. THYMODEPRESSIN (10 µg/kg)
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PR
ES
SII
ON
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UP
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N I
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COMPARISON OF CYCLOSPORIN A AND THYMODEPRESSIN ON GVHD SUPRESSION
(MICE SPLENOMEGALY MODEL)
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* **
Ctrl titers
COMPARISON OF CYCLOSPORIN A AND THYMODEPRESSIN ON AUTOANTIBODY
SUPRESSION (Mercury inducing antibodies to fibrillarin, prophylactic mode)
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PASI 68 PASI 6
Patient B. before treatment
Patient B. after one month
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Patient C. before treatment by Thymodepressin
Patient C. after 4 month(one cycle of treatment)
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Neogen/Stemokine:Neogen/Stemokine: a new generation of immuno and hemo-stimulanta new generation of immuno and hemo-stimulant
Approved in Russia in 2009 Stimulates the immune system Stimulates regeneration of
hemopoiesis (hemopoietic stem cells) after irradiation or chemotherapy
Shows no side effects
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STEMOKINE (NEOGEN) AND G - CSF INFLUENCE ON REPOPULATION OF CFU-S AFTER 7 Gy IRRADIATION
0
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0 9 14 21сутки
CF
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N
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7 Gy
7 Gy+ G-CSF
7 Gy+NEOGEN
DAYS
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Likopid – a potent and safe immunomodulatorLikopid – a potent and safe immunomodulator
• Pronounced immunomodulatory Pronounced immunomodulatory effecteffect
• Minimal side effects, high Minimal side effects, high tolerancetolerance
• Convenient formulation Convenient formulation (1 or 10 mg tablets)(1 or 10 mg tablets)
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secretionsecretion
GMDPGMDP – – NOD2NOD2: : molecular mechanism of action molecular mechanism of action andand signal pathwayssignal pathways
NUCLEUSNUCLEUS
GMDPGMDP
key:key:
CARDCARDNODNODLRRLRRKinaseKinase
NOD2NOD2
GMDPGMDP
peptidoglycanpeptidoglycan
RIP2/RISCRIP2/RISC
1kB1kBNF-kBNF-kB IL-1IL-1proIL-1proIL-1
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INFLUENCE OF PEPTIDES ON HEMOPOIESIS
Suppression by ThymodepressinSuppression by Thymodepressin
Stimulation by NeogenStimulation by Neogen
Stimulation by LikopidStimulation by Likopid Stimulation by ThymogenStimulation by Thymogen
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Topics for discussion:
Pipeline of peptide pharmaceuticals: contribution of Russian science: - Peptide vaccines
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В-В-cellscellsFOOT AND MOUTH DISEASE VIRUS
EPITOPES FOR:
Т-Т-helpershelpers
SYNTHETIC PEPTIDE VACCINE
Site responsible for virus Site responsible for virus receptionreception
PATENTED SYNTHETIC FOOT AND MOUTH DISEASE VACCINE APPROVED FOR VETERINARIAN USE IN RUSSIA
Active principleActive principle - - syntheticsynthetic fragment of the VP1 viral protein acylated by palmitinic acid; fragment of the VP1 viral protein acylated by palmitinic acid;
AdjuvantAdjuvant – – synthetic polymethylsiloxane oil;synthetic polymethylsiloxane oil;
Duration of the protective immunityDuration of the protective immunity – – 1 1 year after single immunization;year after single immunization;
The vaccine is effective against the The vaccine is effective against the А А2222 viral strain in sheep.viral strain in sheep.
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Alzheimer’s disease (AD):Alzheimer’s disease (AD):
Vaccination with synthetic peptide fragment of α7-subunit of the AChR provides a new approach to
anti-AD drug development.
Our proposals:Our proposals:
1) Selected synthetic fragments of Аβ-α7
AChR-Receptor can be used for development of anti-Receptor antibodies
2) Antibodies directed against Receptor
will prevent the Receptor from binding to β-amyloid
3) Neurons will survive
4) Therapeutic vaccine will be developed
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The model of the extracellular N-terminal domain of α7-subunit of the AChR
Peptide I (1-23) 1GEFQRKLYKELVKNYNPLERPVA23
Peptide II (159-168)-(179-188) 159QMQEADISGY168-179IPGKRSERFY188
Peptide III (173-188) 173EWDLVGIPGKRSERFY188
Peptide IV (173-193) 173EWDLVGIPGKRSERFYECCKE193
Synthetic fragments of extracellular N-terminal domain of Synthetic fragments of extracellular N-terminal domain of αα77-subunit of the AChR-subunit of the AChR
EWDLVGIPGKRSERFYECCKE
CH2
HN
CH C
O
NH
CHC
O
C O
H2C
HN
CH C
CH2 OH
O
HN
CH2H2C
H2C
H2C NH2
Peptide IV (173-193) with “built-in” adjuvant
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The level of The level of ββ-amyloid in brain tissues of experimental AD -amyloid in brain tissues of experimental AD
– mice and control (Ct) mice– mice and control (Ct) mice
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Topics for discussion:
Pipeline of peptide pharmaceuticals: contribution of Russian science:
- Oral delivery system
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WHAT IS THE NEXT STEP IN PEPTIDE DEVELOPMENT?
Development of a new generation of small peptide-based pharmaceuticals with increased stability to digestive enzymes resulting in oral availability
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L-Glu-L-Trp - immunostimulant (Thymogen)
-D-Glu-D-Trp - immuno- and hemosuppresant
(Thymodepressin)
Chemical structure of peptide immunomodulatorsChemical structure of peptide immunomodulators
- high selectivity +
- minimal side effects +
- stability per os -
- solubility in aqueous media +
- low toxicity profile +
- non immunogenic +
- molecular mass below 500 D +
- high selectivity
- minimal side effects
- stability per os
- solubility in aqueous media
- low toxicity profile
- non immunogenic
- molecular mass below 500 D
Pfizer's “Ideal formula” :
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R
R
carrier
NH
CO
NH
CO
Linker 1
Linker 2
CH2
NH
Active molecule 1
o
NHCo
CH3
oCH3
Co
H
Active molecule 2
CycloTechnology Platform:
Multifunctional biologically active composition
Variable building blocks
Individual molecules chemically linked to a biocarrier
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CycloTechnology Platform: Biocarrier scaffold + Functional derivatives
Immunology Hematology Neuro-pharmacology
Chemo-pharmacology
- Immunostimulation
- Adjuvant activity
- Vaccination + adjuvant: Conventional vaccines Synthetic vaccines Cancer vaccines
- Hemostimulation
- Stem cell boosting
- Blood cell boosting and harvesting
- Immunosuppression
- Hemopoiesis suppression
- Autoimmune diseases
- Transplantation
- Neuroimmunology
- Drug addiction
- Psychopharmacology: Depression, Stress, Anxiety
Metabolic and
toxicity profile
improvements
for small molecules
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CycloTechnology platform:
New generation of peptide derivativesNew generation of peptide derivatives
- high selectivity +
- minimal side effects +
- stability per os +
- solubility in aqueous media +
- low toxicity profile +
- non immunogenic +
- molecular mass below 500 D +
- high selectivity
- minimal side effects
- stability per os
- solubility in aqueous media
- low toxicity profile
- non immunogenic
- molecular mass below 500 D
Pfizer's “Ideal Formula” :
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“Pharma Bio LLC” Development Plan for 2011-2013
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Set up of pilot GMP facility for peptide synthesis of API and nasal spray
Thymodepressin – clinical trials for new indications: RA, MS, Asthma
Stemokine – clinical trials for new indications : oncology, oncohematology, tuberculosis
Sedatin –Phase I –II clinical trials for the treatment of anxiety and stress
Opilong –Phase I –II clinical trials for the treatment of alcohol dependence
C12-OB – Preclinical development of new synthetic vaccine for the AD immunotherapy
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Layout of GMP pilot facility for peptide API and Nasal sprays
View of future GMP unit of “Pharma Bio”
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Peptide Pharmaceuticals: Development in Russia and Worldwide
JV “Pharma Bio”
Thank you!