discovering multiple novel magic bullets towards ......discovering multiple novel magic bullets...
TRANSCRIPT
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Discovering multiple novel magic bullets towards combinatorial cure of malaria without the shadow of resistance
Malaria Research Laboratory International Centre for Genetic Engineering and Biotechnology (ICGEB) New Delhi [email protected]
Dinkar Sahal
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Malaria parasite is more ancient than we are
What is the nature of malaria parasite that makes it what it is : both ancient and modern at the same time?
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Malaria Parasite has evolved ecclectically & has ventured to Parasitize distant life forms
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Plasmodium falciparum life cycle
Malaria Parasite cycles across mosquito salivary gland
to our liver first & our blood next
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Sinister Repercussions of Malaria:
Gerson Rothschild et al, Cell 162, August 13, 2015
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Quinine
Long before we knew anything
about Malaria the Cichona
plant knew how to treat it
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Artemisinin Artemisia annua
After Cinchona, Artemisia annua emerged as another
plant that knew how to treat malaria
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With so many selfless organisms
providing us with great antimalarial medicines,
how does Malaria continue to play havoc
causing economic and emotional turmoil?
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Quinine
Chloroquine
Amodiaquine
Primaquine
Mefloquine
Pyrimethamine -Sulfadoxine
Halofantrine
Chloroquine Primaquine
Mefloquine
Pyrimethamine
Sulfadoxine
Quinine
Amodiaquine
Halofantrine
Reason: Drugs Against Malaria come,stay for a while and go
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Late
1960s
CQ Resistance
Demise of GMEP
1970s
Late
1950s
The euphoria
Of CQ
GMEP
Poor PK but
very potent &
quite safe.
Improved bioavailability+ more effective
When combined with Mefloquine (ACT)
2005
Resistance to
ACTs
Alarm! ACTs are
on the same
path to
obsolescence
as CQ
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The Paradox of drugs is equally true of antibiotics as well
Every time we use an antibiotic we potentially weaken its effectiveness.
1988 1952 Erythromycin
1953 Tetracycline
1959 1947 Chloramphenicol
1960s 1945/1964 Cephalosporins
1959 1943/1945 Streptomycin
1940s 1930s Sulfonamides
Resistance Discovery/introduction Antibiotic
1948
1988/1993 1956 Vancomycin
1960 Methicillin 1961
1973 1961 Ampicillin
1988 1981/1985 Cefotaxime/ceftazidime
1946 1928/1943 Penicillin
Penicillin
Sulfonamide
Streptomycin
Cephalosporin
Chloramphenicol
Tetracycline
Erythromycin
Vancomycin
Methicillin Ampicillin
Cefotaxime
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Moral of the story: Resistance is like a shadow of drugs
If resistance is like a shadow of drugs, the need
for new drugs becomes a perennial priority
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Consulting Nature for New Drugs Against Malaria
Marine organisms Medicinal Plants Fungi Cyanobacteria
PK
Screening
In vivo efficacy
Structure & Synthesis
Resistance & Selectivity Indices
Sahal’s laboratory
Activity guided isolation
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0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
0 2 4 6 8 10 12 14 16
% parasitemia
RFU
Sybr Green fluorescence is malarial parasitemia
***
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22 * 168 30 * 71
89 167 86 67
10 *** 218 6.5 *** 166 68 66
<1 *** 217 8 *** 165 36 * 65
5 *** 210 32 * 163 68 64
45 209 41 * 160 68 63
29 * 200 32 * 159 37.5 * 62
57 * 199 30 * 145 100 60
37 * 195 95 142 75 59
100 189 41 * 139 90 58
100 185 100 134 30 * 57
100 184 100 125 90 56
26 * 182 100 119 34 * 55
28 * 179 12 ** 115 34 * 54
17 ** 178 30 * 114 Hemolysis 40
25 * 176 66 112 80 22
39 * 175 5 *** 111 100 21
60 174 72 109 65 18
33 * 173 80 107 90 13
8 *** 172 33 * 106 40 * 11
29 * 171 45 104 50 6
22 * 170 15 ** 99 Hemolysis 3
5 *** 169 60 72 10 *** 2
IC 50
(g/ml)
Crude Marine
Extract
IC 50 (g/ml)
Crude Marine
Extract
IC 50 (g/ml)
Crude Marine
Extract
IC50 Values of Marine Extracts Showing Antiplasmodial Activity (SYBR Green Method)
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1
2 3
5
4 6
7
8
9
10 11
12
13 14 15
16
17
18 19
IC50 Crude : 17 µg/ml Amount: 2g (Sup 1.5 g) Flow rate: 62 ml/min 214/254 Recovered 1300/1500
178
frc mg
IC50
( g/ml) 1-3 687 NA
4 20 17.09
5 11 9.14
6 16 NA
7 16 20
8 65 7.13
9 32 NA
10 17 1.78
11 8 12.5
12 42 1.72
13 29 6.22
14 26 1.55
15 16 1.55
16 22 1.77
17 15 1.9
18 6 3.3
19 5 6.25
20 300 7.10
Antiplasmodial activity guided Reverse Phase HPLC separation
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169.10 0.13
169.18 &19 0.21
169.14 0.7
169.20 0.8
169.17 1.1
169.11 1.2
169.15 2.7
169.16 2.9
169.13 2.6
169.12 4
169.8 & 22 5 169.21 4.8
169.23 10.5
178.10 0.39 178.17 0.39
178.14 1.5 178.15 1.5
178.12 1.7
178.16 1.8
178.18 3.3
178.19 6.25
178.13 6.22
178.8 7.13
178.5 9.14
178.11 12.5
169.10 0.13
Fraction no IC50 (g/ml)
Extract no
169 & 178 have a rich spectrum of potent antiplasmodials that
are lethal against Chloroquine resistant Plasmodium falciparum
: potent against Chloroquine resistant Pf RKL9
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30% B
75% B
50% B
75% B 0.5%/min
0.75%/min
45% B
70% B 0.5%/min
62 ml/min 15 µm
10 ml/min 15 µm
1 ml/min 5 µm
IC50
17 g/ml
IC50
1.7 g/ml
IC50
0.5 g/ml
2 g
17 mg
50 µg
Antiplasmodial activity guided purification of 178.10
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Antiplasmodial molecules purified from 178
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Sr. No Sample
ID
P. falciparum
IC50 (g/ml)
HeLa
TC50
(g/ml)
Selectivity
index HeLaTC50 / Pf3D7 IC50
3D7 INDO
1 178D3 1.2 1.4 >100 > 83
2 178M3 0.7 0.9 >100 >100
3 178M4 0.9 1 >100 >142
4 178-10 0.39 0.39 >50 >128
5 178-13-1 0.54 0.5 >50 >100
6 178-13-2 0.6 0.7 >50 >83
7 178-17-1 0.42 1 12.5 28
8 178-17-4 0.84 1 17 17
9 178-17-6 0.78 0.9 18 20
Antiplasmodial potencies, mammalian cell cytotoxicities
and selectivity indices of ME178 derived molecules.
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In vivo efficacy
PK
Resistance & Selectivity Indices
Nature inspired chemical libraries based on Chalcones, Stilbenes, Dibenzylideneacetones, Acridines, Quinolines, Pyrimidines, Cryptolepins, Azoles,, Aplysinopsins,, Chromones,, Bisindoles, Indoquinolines , Phloroglucinols ,, Dendrimeric peptides & metallic nanoparticles
Nature inspired chemical synthesis of new pharmacophores Against Malaria
Screening
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In vivo efficacy
PK
Resistance & Selectivity Indices
Nature inspired chemical libraries based on
Nature inspired chemical synthesis of new pharmacophores Against Malaria
Screening
Chalcones, Stilbenes, Dibenzylideneacetones,
Acridines, Quinolines, Pyrimidines, Cryptolepins,
Azoles,, Aplysinopsins,, Chromones,, Bisindoles, Indoquinolines
, Phloroglucinols ,,
Dendrimeric peptides metallic nanoparticles
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Cryptolepine IIIM-MCD-668
0.1 150
Pf 3D7IC50 (M) Selectivity index
Aminoquinoline S5
0.34 217
N
N
O
MeO
Imidazole GVM-GV-010
0.75 >133
Stilbene i10-183
0.9 >111
Chalcone i9-36
2 50
Aplysynopsin IIIM-MCD-680
2.8 >36
Bisindole IIIM-MCD-422
0.47 213
Pyrimidine IIIM/724/ 1582/CF/08
IC50 : 0.69 µM/ --
0.69 ---
A glimpse of chemically synthesized molecules active against malaria parasite
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0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Untreated control
GV10
Days
% P
ara
site
mia
Average survival time
(Days)
Untreated Control GV10
20.2 ± 2.3 28.6 ± 4.2
IV injection of Infected
RBC (105 )
GV10
In vivo antimalarial activity of orally administered GV10 in P. berghi (ANKA) infected Balb/C Mice
Vehicle: 2% (Hydroxypropyl) methyl cellulose with 2 % Tween 80 in Normal saline
Dose : 50 mg/KgBW in 200 µL /mouse
Route : Oral
Mice/ Group: 5 ♀
IC50 ( M) Pf3D7: 0.75 µM ; Pf INDO: 0.8 µM ; Selectivity Index: >133.3 (HeLa)
0
5
10
15
20
25
30
35
40
5 7 9 11 13 15 19
%
Pa
rasi
tem
ia S
up
pre
ssio
n
Days
N
N
O
MeO
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With both Nature and the ingenious chemists
on our side
Why have we allowed Malaria to
continue to rattle us?
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The 19th century concept of “magic bullets” paid an important role in standardization of pharmaceuticals. Drugs would work perfectly as long as the pathogen was “ the same”.
But such “single magic bullet” would stop working when the pathogen learnt to survive with mutations.
The two halves of the 19th century
Drug sensitive
Drug Resistant
Benefits of 1st half were undone in the 2nd half of 19th century by proliferation of resistance to antibiotics, Antimalarials, Insecticides & herbicides.
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As long as crude extracts of medicinal plants were in use, we had no problem of resistance
Resistance became common place since the time we started using modern medicine which professed the use purified Single molecule based drugs which worked like magic bullets
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Has rational scientific thinking that
pulled drugs out from plants been
responsible for drug resistance?
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WHO’s warning is valid
because of low Artemisinin content of :
Juice extraction Tea Infusion
But what about oral consumption
of dried leaves of the whole plant?
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PNAS 2015
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Control
Artemisinin (AN) treated
Whole-plant Artemisia annua restricts the growth Artemisinin resistant P.yeolii (ART) much better than pure Artemisinin each at the high dose of 120 mg/Kg Artemisinin
A.Annua whole plant (WP) treated
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At the lower dose of 24 mg/Kg Artemisinin, pure Artemisinin is ineffective while the whole plant shows growth retardation of Artemisinin resistant P.yeolii (ART)
treated
treated
Untreated Control
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120 mg/Kg
24 mg/Kg
ANHI= WPLO
HI
LO
120 AN/24WP=5. The plant is 5 times more effective than purified Artemisinin in restricting the growth of Artemisinin resistant P.yeolii (ART) Malaria parasite.
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AN-resistant P.yoelii curative treatment 120 mg/Kg of ANHi or WPHi daily for nine consecutive days starting on day 2 post infection
vs
At equivalent dose of Artemisinin, Whole plant is far more effective than pure Artemisinin in killing the Artemisnin resistant malaria parsaite
ANHI
WPHI
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Could nonpharmaceutical whole plant forms
of therapy abolish the shadow
of resistance associated with monotherapies?
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Artificial Evolution Experiment to compare rates at which resistance arises against Artemisinin VS Artemisnin annua
2% DT: Difference in time to reach 2% parasitemia between
treated and untreated animals
P chabadui (Artemisinin sensitive) infected mice
Untreated
1
2
Passage 25
Artemisinin treated
Passaging blood from mouse to mouse
Art-Treated
% P
aras
ite
mia
1
2 Passage 1
Time
Passage 50
2
1
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200 mg/Kg
100 mg/Kg
A annua
Whole plant treatment of 100 mg/Kg is more resilient than 200 mg/Kg of Pure Artemisinin in resisting the emergence of resistance
2%DT
Stable resistance Stable resistance
No Stable resistance yet
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What may cause the whole Plant to be more potent & reliable than the plant derived magic bullet alone?
Artemisia annua
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artemetin Casticin
Chrysosplenetin
Chrysosplenol D
cirsiliol
Eupatorin
Isovitexin
Kaempferol
Luteolin
Myricetin
Rutin
Quercetin
Contributory factors: (i) A.annua flavinoids with Antimalarial activity
Plant based Artemisinin combination therapy (pAct) can offer rich prospects of Synergy
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: In serum 60 min post pACT or pure Artemisinin gavage
Chou contains soy, oats, wheat,beet pulp, corn etc
(ii) Whole Plant enhances bioavailablity of its “magic bullet”
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(iii) Animals and Plants use interestingly different biological warfare
strategies to fight similar pathogens
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(iv)That these defences are also effective at killing a
mammalian blood borne protozoan parasite seems
coincidental; but there is a plausible evolutionary
explanation for this cross- species protection.
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In retrospect, In matters of biological warfare and drugs, Plants are more full of wisdom than us humans
Because if Plants had followed the pharmaceutical model of serial production of single-component protection against its enemy, they would have become extinct long ago.
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Pharmacutical based monotherapeutics
Plant based polytherapeutics
Predetermined content, fully standardized
Variable content, lack of standardization
Lower potency Greater potency
Resistance inevitable
Resistance is less frequent
Consistent with a fast life style
Work well where life is in harmony with Nature
Generally safe Friendly and toxic molecules may coexist
Our century needs a sense of direction in the use of drugs
Answer: By identifying the virtues of each molecule in a repertoire of pure magic bullets, & mixing them all before making a composite pill
for the patient.
How can we combine the virtues of single component therapeutics with the virtues of the multicomponent therapeutics ?
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Resistance
Time
Magic Bullet
Greater Potency & Prolonged efficacy
Multiple
Magic
Bullets
Need to combine the fervour of Paul Ehrlich for magic bullet with the wisdom of using multiple magic bullets
Synergy
Enhancer of bioavailability