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BIOMEDICAL RESEARCH CENTER
BRC
UH
FVZ
UHK Faf
LFHK
University Hospital HK
Faculty of Military Health Sciences
Pharmaceutical faculty
Faculty of Medicine
Faculty of Science UHK Faculty of Informactics and
Managment UHK (Biomedical Informatics
Center)
BIOMEDICAL RESEARCH CENTER
Brief history: •April 2011 - Established To prevent outflow of scientists (3 full positions divided into 6 people)
•February 2012 - Laboratory facility – EU postdoc
program started (4 full positions gained)
•October 2013 - 30 empoyees (senior and junior
scientists, PhD students, lab. assistants; total 3.2 positions – full/part time)
- total 50-60 people (students and other helpers)
BIOMEDICAL RESEARCH CENTER
AIMS:
Support basic research in the Hospital (drug development, analysis, assessment etc.)
Service for the clinics and applied research (proteomics, pharmacokinetics etc.)
Education (pre and postgraduated students, interships, seminars)
BIOMEDICAL RESEARCH CENTER
Projects: Currently solving 11 project (including internal) 6 internal cooperations (within Hospital) 8 external cooperations (in CZ)
Funding: • Grant Agency of CZ, Grant agencies under Ministry of Health, Defence,
Education etc. • Private sector (organic synthesis, cytotoxicity, acute toxicity etc)
Incomes: Projects (10-20% for the hospital) Publications (depending on the IF) Services for fee
...what we get, we need to pay back
BIOMEDICAL RESEARCH CENTER
Cooperations:
Canada
USA
Brazil
Croatia Sweden France Germany Serbia Hungary
Korea
Singapore
India
UAE
UK Italy Slovakia
...30 to 40 IF papers per year
Představení proteomické skupiny Centra Biomedicínského Výzkumu
Chemical
synthesis
Pharmacokinetics
Proteomics
In vitro biologial
assessment
D
r
u
g
D
e
v
e
l
o
p
m
e
n
t
BIOMEDICAL RESEARCH CENTER
In vivo assesment,
toxicity
DRUG DEVELOPMENT
Drug discovery
Preclinical Trials
Clinical trials
(I.-III. phase)
Practical use
(IV. phase)
12-15 years, aprox. 1 mld USD
BRC
Targeted synthesis Design and Synthesis
In-vitro evaluation
Toxicity
1st selection
Pharmacokinetics
In-vivo
?
2nd selection
„Drug candidates“- recommendation for preclinical trials, commercialization, ip protection
BRC - DRUG DESIGN
BRC - DRUG DESIGN
• targeted synthesis (in silico methods – molecular docking, QSAR) • modification of known drugs • isolation from the plants
Topics
AChE MODULATORS
Alzheimer´s Myasthenia
gravis Antidotes
ABAD inhibitors
Alzheimer´s
Detergents
Desinfection
Decon Anticancer
MOLECULAR DOCKING
• Enzyme known structure (enzym, receptor)- RTG; www.pbd.org • docking of drug candidates into the enzyme cavity
N
NH2
N
NH2
H3CO
Tacrine 7-MEOTA IC50: 0.5 ± 0.1 uM IC50: 10.5 ± 2 uM
CHEMICAL SYNTHESIS
Organophosporus prophylaxis
Myastenia gravis
Charged: Peripherally active AChE inhibitors
N (A) N 2 X
R
HON=HC
ANTIDOTES
Oxime moiety
IN VITRO SCREENING
Alzheimer‘ disease
• Inhibition of AChE, Beta-secretase, Prolyl-oligopeptidase,
• Affinity to M a N rcp.
• Antioxidant activity
• Inhibition of Abeta formation (SAV Kosice)
• Inhibition of ABAD (St. Andrews, UK)
• Etc.
AChE reactivators
• Inhibition of AChE
• Reactivation screening (10-3 a 10-
5M) against nerve agents
• Kinetics
• Corellation with standards (obidoxime, HI-6 etc.)
IN VITRO SCREENING
PERIPHERAL AChE INHIBITORS
• ACHE inhibitors for:
• Myasthenia gravis
• Prophylaxis against Nerve Agents
• STAT3 inhibitors
• ATM inhibitors
• Cooperation Academy of Science
DETERGENTS
•Desinfection means -CMC->MIC na G+ a G- strains, fungi
•Decontamination means -CMC
•Stabilisation of gold nanoparticles
•hypertermal anticancer therapy
•preparation of SERS active substrates
•Novel topic
•Novel adjuvans for vaccines (TLR4 receptor antagonists)
ANTICANCER THERAPY
ADJUVANTS
Clinical proteomics Quantitative and qualitative description of the protein content in the samples using LCMS Explorative analysis •What protiens are in a sample?= identification •What is the difference in quantities of different proteins in a samples (treated vs non-treated group) = quantification
Targeted analysis •I know what I´m looking for and what is the level of this protein in different samples
BRC - PROTEOMICS
PROTEOMICS –projects
1)Proteomic analysis of amniotic fluid samples from preterm birth patients 2)Protein markers of inflammatory complications during preterm birth 3) Proteomic analysis of different kind of thrombi in case of heart attack 4) Proteomic analysis of the rat brains chronically exposed to low doses of pesticides (gulf-war syndrom) 5) Risk assassment based on the proteomic analysis for the pituitary adenome relapses (retrospective study) 6) Proteomic analysis of different kind of colorectal cancers • With/without biological treatment • Retrospective study of the relepses of the CoCa
Tambor, V. et al. J Proteomics 2012, 3, 857 Tambor, V. et al. PLoS ONE 2012, 7
BEFORE INTOXICATION
AFTER INTOXICATION
Nerve Agent
Prophylaxis (= Pretreatment) -Pyridostigmine, Physostigmine
-Transant (HI-6)
-PANPAL, etc.
Decontamination -reactive or non-reactive
-personal or mass
Treatment -anticholinergic drugs
-acetylcholinesterase reactivators
-anticonvulsants
MILITARY RESEARCH FOCUS
K-OXIMES
Reactivators in progress – K027 – excellent reactivator for OP pesticide poisoning
– K203 – excellent reactivator for tabun poisoning
AUTOINJECTOR
Three-chambered autoinjector
1. chamber - oxime HI-6
2. chamber - atropine
3. chamber - diazepam
Autoinjector patented.
www.chemprotect.eu
BChE REACTIVATORS
• Potent and „broad-spectrum“ reactivators of human BChE inhibited
with paraoxon, dichlorvos, sarin, cyclosarin, tabun and VX
• If possible, aim to develop broad spectrum reactivators for both
AChE and BChE
• More than 100 different structures
CH
NOH
N+
R1
n
R1
=
R2
N+
R2
,
Pseudo-catalytic bioscavengers
NUCLEOPHILIC DETERGENTS
Detergent and
Nucleophile in
one Molecule Non-functionalized
Detergents
Non-functionalized Detergents
+ Nucleophile
+
Three different types of systems:
1. 2. 3.
• Skin penetration studies • In vitro x In vivo • Franz-type diffusion cells • Pigs, rats
0
0,02
0,04
0,06
0,08
0,1
0,12
0 100 200 300 400 500 600
Time (min)
Am
ou
nt p
en
etr
ate
d (
%)
5 min
60 min
2 min
30 min
permeation
Paraoxon
Micelle Creation:
DECONTAMINATION MEANS
HVĚZDA (trans. STAR)
• Bi-component mixture
• Decontamination of warfare agents G, V, H, biological agens – e.g.
spores of B. anthracis (antrax)
• Suitable for skin and common surfaces
Active substances:
Quaternary ammonium salts (as surfactant),
hydrogen peroxide
Users:
• Fire Rescue Service of CR, Army of CR, NATO NRF 3
(2004), civil use – broad spectrum disinfection