Chemical Biology of Ion Transport Van Nguyen 1
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Chemical Biology of Ion TransportVan Nguyen
1
Chemical biology of ion transport
Background
Viral transport
Bacterial transport
Eukaryotic transport
2
Ion transport across cell membranes
ATP ADP + Pi
ClosedOpen
ATP-powered pump100 – 103 ions/sActive transport
Ion channel107 – 108 ions/sPassive transport
Transporter102 – 104 ions/s
Responsible for: • transepithelial transport of salt and water• regulation of cytoplasmic or vesicular ion concentration • regulation of cellular volume and pH• chemical signaling
Marieb, E.N; Hoehn, K. Human anatomy and physiology; Pearson: New York, 2013. 3
simple diffusion ion carrier ion channel
Chemical biology of ion transport BackgroundViral transportBacterial transportEukaryotic transport
4
Influenza A entry mechanism
5
Under acidic condition: • Endosomal membrane fuses with viral envelope• M1 protein releases virus RNA, allow virus to replicate in nucleus
Imagestakenfromwww.virology.ws
H+
H+
M1M2
M2 transmembrane segment
• 4 parallel monomers • Regulate pH by transporting proton• Crucial for viral replication
6Pielak, R. M; Chou, J. J. Biochim. Biophys. Acta, 2011, 1808, 522-529.
Inhibitors of M2NH2
H2N
Amantadine
Rimantadine
7
Amantadineor Rimantadine
• Approved by FDA in 1976 • No longer effective
Tisdale, M. Antimicrobial drug resistance; Springer, 2009
Image taken from www.virology.ws
Water network in M2 transmembrane segment
8
viral exterior
Val27 valve
Ala30, Ser31
Ala34
Entry cluster
His37 box
Bridging cluster
Trp basket
Exit cluster
Asp44, Arg45
Acharya, R.; Carnevale, V.; Fiorin, G.; Levine, B. G.; Polishchuk, A.L.; Balannik, V.; Samish, I.; Lamb, R. A.; Pinto, L. H.; DeGrado, W. L.; Klein, M. L. Proc. Natl. Acad. Sci., 2010, 107, 15075-15080
G34A mutant
Asymmetrical transport activity of M2
9
Acharya, R.; Carnevale, V.; Fiorin, G.; Levine, B. G.; Polishchuk, A.L.; Balannik, V.; Samish, I.; Lamb, R. A.; Pinto, L. H.; DeGrado, W. L.; Klein, M. L. Proc. Natl. Acad. Sci., 2010, 107, 15075-15080
pH 8.2 pH 6.5 pH 5.01st His37 protonated
decreasing pH
3rd His37 protonated 4th His37 protonated
Val27
His37
Trp41
Water network in M2TM
10Thomaston, J. L.; Alfonso-Prieto, M.; Woldeyes, R. A.; Fraser, J. S.; Klein, M. L.; DeGrado, W. F. Proc. Natl. Acad. Sci., 2015, 112, 14260-14265.
Cryogenic temperatureHigh pH Low pH
Room temperatureHigh pH Low pH
Val27
Ser31
Gly34
His37
Trp41
Val27
Ser31
Gly34
His37
Trp41
16.8 Å
Water network in wild-type and S31N mutant M2
11
S31N natural mutant of M2 wild-type M2
Acharya, R.; Carnevale, V.; Fiorin, G.; Levine, B. G.; Polishchuk, A.L.; Balannik, V.; Samish, I.; Lamb, R. A.; Pinto, L. H.; DeGrado, W. L.; Klein, M. L. Proc. Natl. Acad. Sci., 2010, 107, 15075-15080.Thomaston, J. L.; Alfonso-Prieto, M.; Woldeyes, R. A.; Fraser, J. S.; Klein, M. L.; DeGrado, W. F. Proc. Natl. Acad. Sci., 2015, 112, 14260-14265.Thomaston, J. L.; DeGrado, W. F. Protein Sci. 2016, 25, 1551-1554.
Asn31 box by H-bonding
Amantadine binding pocket in wild-type M2
12
Gly34
Ser31
pH5.3 pH7.5
Das, K.; Aramini, J. M.; Ma, L.; Krug, R. M.; Arnold, E. Nature Struc. Mol. Biol. 2010, 17, 530-538.
Amantadine in S31N mutant M2
13
• Replacing serine by asparagine:• More hydrophilic – reduce interaction
with hydrophobic cage of amantadine • Longer chain – steric hindrance to drug
binding pocket
Das, K.; Aramini, J. M.; Ma, L.; Krug, R. M.; Arnold, E. Nature Struc. Mol. Biol. 2010, 17, 530-538. Thomaston, J. L.; Alfonso-Prieto, M.; Woldeyes, R. A.; Fraser, J. S.; Klein, M. L.; DeGrado, W. F. Proc. Natl. Acad. Sci., 2015, 112, 14260-14265.Thomaston, J. L.; DeGrado, W. F. Protein Sci. 2016, 25, 1551-1554.
NH2
Asn31
ONH3
O
HO
Serine
ONH3
O
AsparagineO
H2N
Developing M2 inhibitors of S31N influenza A
14
Approach 1: Introduce direct/water mediated H-bonding or electrostatic interactions with backbone of M2 channel
to induce conformational change of Asn31Approach 2: Increase the polarity to enhance binding affinity
of adamantyl group
Wang, J.; Wu, Y.; Ma, C.; Fiorin, G.; Pinto, L.H.; Lamb, R.A.; Klein, M. L.; DeGrado, W. F. J. Med. Chem. 2013, 56, 2804-2812Thomaston, J. L.; DeGrado, W. F. Protein Sci. 2016, 25, 1551-1554
NH2 HN
warhead
Amantadine
Approach 1
Approach 2
To overcomeS31N resistance
Developing M2 inhibitors of S31N influenza A
15
effective inhibitor of S31N
Wang, J.; Wu, Y.; Ma, C.; Fiorin, G.; Pinto, L.H.; Lamb, R.A.; Klein, M. L.; DeGrado, W. F. J. Med. Chem. 2013, 56, 2804-2812Li, F.; Ma, C.; DeGrado, W. F.; Wang, J. J. Med. Chem. 2016, 59, 1207-1216
V27
N31
G34
H2N
ON
S
Inhibitor development strategy
16
Li, F.; Ma, C.; DeGrado, W. F.; Wang, J. J. Med. Chem. 2016, 59, 1207-1216
H2N
ON
SS
OO
NO
N NO
N NS
SN
OH
OH OH HOOH
oxazole oxadiazole thiadiazole thiazole
Potential inhibitors of S31N Influenza A
HN
ON
S
HN
ON
S
HN
ON
S
HN
ON
S
OHOH OH OH
HO
H3CO
30b 30f 30g 30h
17Li, F.; Ma, C.; DeGrado, W. F.; Wang, J. J. Med. Chem. 2016, 59, 1207-1216
% p
laqu
e fo
rmat
ion
log(X nM)
30g EC50 = 404 nM30f EC50 = 510 nM30b EC50 = 727 nM30h EC50 = 2500 nM
Chemical biology of ion transport
BackgroundViral transportBacterial transportEukaryotic transport
18
M2 channel Influenza A
Siderophores – iron chelating agents in bacteria
• Produced by bacteria under iron-depriving conditions• Couple with specific receptor protein to transport siderophore-iron
complex into cell• Essential for bacteria to establish host-parasite relationship in mammalian
cells
19Nagota, B.; Vedpathak, D. Eur. J. Gen. Med., 2011, 8, 229-235Raymond, K. N.; Allred, B. E.; Sia, A. K. Acc. Chem. Res. 2015, 48, 2496-2505
Second siderophore, iron loaded
initially bound siderophore, iron free
Outer membrane Receptor
A
CD
B
Release
iron loaded, siderophore binding
Conformationalchange
Fe3+
exchange
20
Classes of siderophores
Raymond, K. N.; Allred, B. E.; Sia, A. K. Acc. Chem. Res. 2015, 48, 2496-2505
Enterobactin
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
Catecholates
HNN
NHO O NHO
O
O OH
HO
OH
HN N
NH
N
CO2H
OH
O
OO
O
OHOH
CO2H
CO2H
Hydroxamates Carboxylates
Enterobactin-iron complex
∆ - enterobactin21Raymond, K. N.; Dertz, E. A.; Kim, S. S. Proc. Natl. Acad. Sci., 2003, 100, 3584-3588
O
O
O NH
FeO
O O
O
HN O
O
OO
O
O
O
Kd = 1052 M-1
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
Siderophores as treatment for iron overload diseases
• Iron overload caused by:• Blood transfusions required to prevent anaemias, such as
thalassemia major• Genetic defects that increase iron absorption from diet
• Main criteria of ideal iron chelator• High affinity for iron and chelating efficiency• Oral bioavailability • Tissue and cell penetration
22Crisponi, G.; Remelli, M. Coor. Chem. Rev., 2008, 252, 1225-1240
Most natural siderophores unqualified to be drug
Lipinski’s rule:• Molecular weight: 500 • logP < 5• H-bond donors: 5• H bond acceptors: 10
23
MW: 564 logP < 3H-bond donors: 8H bond acceptors: 14
MW: 404logP < 3H-bond donors: 6H-bond acceptors: 12
MW: 669 logP < 3H-bond donors: 9H bond acceptors: 18
Crisponi, G.; Remelli, M. Coor. Chem. Rev., 2008, 252, 1225-1240
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
Catecholates
HNN
NHO O NHO
O
O OH
HO
OH
HN N
NH
N
CO2H
OH
O
OO
O
OHOH
CO2H
CO2H
Hydroxamates Carboxylates
Current drug treatment for iron overload diseases
24Crisponi, G.; Remelli, M. Coor. Chem. Rev., 2008, 252, 1225-1240
H2N N
OH
O
NH
O
N
O
HN
O
NOH
O CH3
DesferalIsolated from
Streptomyces pilosus
N
O
CH3
OH
CH3
Deferiprone
N
N
N
OH HO
ICL670 or Exjade
OH
OOH
Discovery of siderophore-peptide antibiotic MccE492m
25
cSGSG SSSTASNYGS GSGNWSPGILVPIPVNVPGH DILGQGVTQLAGGAAGLAAS GLGGPAGLAAGWAMNNGLDN LLQTNPDTEG
MccE492Peptide antibiotic
Linear enterobactin-MccE492 conjugate with greater antibiotic potency, found in K. pneumoniae
cSGSG SSSTASNYGS GSGNWSPGILVPIPVNVPGH DILGQGVTQLAGGAAGLAAS GLGGPAGLAAGWAMNNGLDN LLQTNPDTEG
MccE492m
Lorenzo, V.; Pugsley, A. P. Antimicro. Age. Chemo. 1985, 27, 666-669
OHOO O
O
OHN
NHHN
O
O
O
OHOH
HO
HO
OHOH
OH
O
HOHOHO
OO
Iron transport by enterobactin in E. coli
26
Outer membrane
Cytoplasm membrane
Fep A
Fep B
channelATPase FepC
Fes
ExbD
ExbB
TonB
FepG
FepD
Raymond, K.N.; Dertz, E. A.; Kim, S. S. Proc. Natl. Acad. Sci., 2003, 100, 3584-3588
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
HOHN
O
OHO
OH
OH
3
O
O
O NH
FeO
O O
O
HN O
O
OO
O
O
O
O
O
O NH
FeO
O O
O
HN O
O
OO
O
O
O
Fe3+
Enterobactin
Kd(FeEnt-FepA) = 0.2 nM
Siderocalin as a challenge for enterobactin-antibiotic conjugates
27
• Siderocalin – human immuno protein• First line of defense against bacteria• Trapping enterobactin by binding
2,3-catechol amides• Kd(FeEnt-siderocalin) = 0.4-0.5 nM
Raymond, K. N.; Allred, B. E.; Sia, A. K. Acc. Chem. Res., 2015, 48, 2496-2505
K134
K125
R81
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HORaymond, K.N.; Dertz, E. A.; Kim, S. S. Proc. Natl. Acad. Sci., 2003, 100, 3584-3588
Glucosylated enterobactin
28
Salmochelin S4 or diglucosylated enterobactin
(DGE) found in Salmonella species and
other pathogenic bacteria
monoglucosylated enterobactin(MGE)
Glucose increases steric of enterobactin, avoiding captured by siderocalin
Chairatana, P.; Zheng, T.; Nolan, E. M. Chem. Sci., 2015, 6, 4458-4471
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
O
OHHOHO
OH
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
O
OHHOHO
OH
O OH
OHHO
HO
Antibiotic-ent-glc conjugates
29Chairatana, P.; Zheng, T.; Nolan, E. M. Chem. Sci., 2015, 6, 4458-4471
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
O
HNON
N NONH
O
NsCO2H
HO
R
3
R = H: AmpicillinR = OH: Amoxicillin
hydrolyzable group O OH
OHHO
HO
O OH
HO OHHO
diglucosylated-enterobactin-antibiotics (DGE)
Antibiotic activity against human pathogenic E. coli
30
Amp-Ent-diGlu is 1000-fold more active than Ampicilin
Chairatana, P.; Zheng, T.; Nolan, E. M. Chem. Sci., 2015, 6, 4458-4471
CFT073 UTI89
OD
600
OD
600
0.16
0.12
0.08
0.04
0.00
0.20
0.00
0.05
0.10
0.15
0 010-10 10-9 10-8 10-7 10-6 10-5 10-4
Concentration (M)10-10 10-9 10-8 10-7 10-6 10-5 10-4
Concentration (M)
ampicillinenterobactin-ampicillin
monoglucosylated enterobactin-ampicillindiglucosylated enterobactin-ampicillin
Human pathogenic vs. non-pathogenic E. coli
31
Ec K-12 vs CFT073 Ec K-12 vs UTI89
CFU
/mL
Chairatana, P.; Zheng, T.; Nolan, E. M. Chem. Sci., 2015, 6, 4458-4471
CFU
/mL
1010
109
108
107
106
105
104
Ec K-12 Ec CFT073 Ec K-12 Ec CFT073 Ec K-12 Ec CFT073 Ec K-12 Ec CFT0731:1 mixed culture 1:1 mixed culture
1010
109
108
107
106
105
104
untreatedampicillinenterobactin-ampicillin
monoglucosylated enterobactin-ampicillin
diglucosylated enterobactin-ampicillin
Biosynthesis of enterobactin
32Gehring, A. M.; Bradley, K. A.; Walsh, C. T. Biochemistry., 1997, 36, 8495-8503
O OH
OHO
O
OH
O OH
OHO
O
OH
OHO OH
OH
OH
O OH
OH
OH O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
Ent Cisochorismate
synthetase, Mg2+
Ent B2,3-dihydro-2,3-
dihydroxybenzoate synthetase
Pyruvate
Ent A, NAD+
2,3-dihydro-2,3-dihydrobenzoate dehydrogenase Ent E,F,D
L-Lysine
Ent E: 2,3-dihydroxybenzoate- AMP ligaseEnt D: phosphopantetheinyl transferaseEnt F: seryl-AMP ligase
H2N
NH3
O
O
L-Lysine
Chemoenzymatic synthesis of glucosylated enterobactin
33Lee, A. A.; Chen, Y. S.; Ekalestari, E.; Ho, S. Y.; Hsu, N. S.; Kuo, T. F.; Wang, T. A. Angew. Chem. Int. Ed. 2016, 55, 12338-12342
OCl
NO2
OOH
HOHO
HO OOH
HOHO
UDPHO
UDP
OCl
NO22-chloro-4-nitrophenyl glycoside
O NONH
O
OPO
OO
PO
OHO
UDP-Glc
UDP =
oleandomycinglycosyltransferase
Chemoenzymatic synthesis of glucosylated enterobactin
34Lee, A. A.; Chen, Y. S.; Ekalestari, E.; Ho, S. Y.; Hsu, N. S.; Kuo, T. F.; Wang, T. A. Angew. Chem. Int. Ed. 2016, 55, 12338-12342
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
O
O
O
O
O
O
NHHN
HN
O
O
O
OHOH
OHOH
HO
HO
OOH
OH
HOHOUDP-Glc
UDP
enterobactin(Ent) R2
glucosyltransferase
R1
R1 R2 ProductH
GlcGlc
HH
Glc
(Glc)1Ent(Glc)2Ent(Glc)3Ent
Chemical biology of ion transport
BackgroundViral transportBacterial transportEukaryotic transport
35
M2 channel Influenza A
EnterobactinE. coli
What is cystic fibrosis?
• A genetic disease • Persistent lung infections• U.S.: 30,000 patients• Worldwide: 70,000 patients• 1,000 new cases diagnosed with cystic fibrosis each year
36
Cystic fibrosis transmembrane conductance
37
• Cystic fibrosis transmembrane conductance regulator (CFTR gene) is mutated
• Defective chloride ion channel• Disrupting mucus flow• Clogging airway and trapping bacteria• Surface of lung cell dehydrated
Restoring CFTR chloride channel as CF treatment
ATP ADP + Pi
ClosedOpen
ATP-powered pump100 – 103 ions/sActive transport
Ion channel107 – 108 ions/sPassive transport
Transporter102 – 104 ions/s
Marieb, E.N; Hoehn, K. Human anatomy and physiology; Pearson: New York, 2013. 38
simple diffusion ion carrier ion channel
Synthetic anionphores
Synthetic ion channel
Strategy 1: Amphotericin B as ion channel• Isolated from Streptomyces nodosus in 1955• Highly effective antifungal• Kill fungi by binding and forming a channel to
permeabilize cell membranes• Non-selective ion channel
39Wildeman, E. L.; Gonen, T.; Rienstra, C. M.; Burke, M. D. Nature. Chem. Biol., 2014, 10, 400-406.Palacios, D. S.; Anderson, T. M.; Burke, M.D. J. Am. Chem. Soc., 2007, 129, 13804-13805.
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
O O
OH NH2OH
Me
Amphotericin BAmB
mycosamine
Derivative of AmB to study ion channel activity
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
O O
OH NH2OH
Me
Amphotericin BAmB
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
OH
mycosamine
AmdeBno mycosamine
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeH Me
O O
OH NH2OH
Me
mycosamine
C35deOAmBno OH at C35
3535
40
Wildeman, E. L.; Gonen, T.; Rienstra, C. M.; Burke, M. D. Nature. Chem. Biol. 2014, 10, 400-406.
Channel activity of AmB and derivatives
41
Only AmB show channel activityby releasing K+
Gray, K. C.; Palacios, D. S.; Dailey, I.; Endo, M. M.; Uno, B. E.; Wilcock, B. C.; Burke, M. D. Proc. Natl. Acad. Sci., 2012, 109, 2234-2238.
DMSOAmB 1µM
C35deOAmB 1µMC35deOAmB 10µM
Perc
ent o
f Max
K+
Rele
ase
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6
Time (min)
Derivative of AmB to study ion channel mechanisms
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
O O
OH NH2OH
Me
Amphotericin BAmB
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
OH
mycosamine
AmdeBno mycosamine
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeH Me
O O
OH NH2OH
Me
mycosamine
C35deOAmBno OH at C35
3535
42
no channel formation
Wildeman, E. L.; Gonen, T.; Rienstra, C. M.; Burke, M. D. Nature. Chem. Biol. 2014, 10, 400-406.Cioffi, A. G.; Hou, J.; Grillo, A. S.; Diaz, K. A.; Burke M. D. J. Am. Chem. Soc. 2015, 137, 10096-10099.
AmB restores activity of defective yeast S. cerevisiae
43
• S. cerevisae yeast missing trk1∆trk2∆ potassium transporters –can’t growth
• Minimum concentration of AmB required to restore growing rate of yeast is 0.125 µM
trk1∆trk2∆ + AmBtrk1∆trk2∆ + C35deOAmB
concentration (µM)
OD
600
max
OD
600
wildtype
trk1∆trk2∆
43
trk1∆trk2∆+AmB
NS
Cioffi, A. G.; Hou, J.; Grillo, A. S.; Diaz, K. A.; Burke M. D. J. Am. Chem. Soc. 2015, 137, 10096-10099.
1.21.0
0.80.60.4
0.20.0
1.21.0
0.80.60.4
0.20.0
1.4
1.21.0
0.80.6
0.4
0.20.0
0 0.25 0.5 0.75 1
AmB restores CFTR Cl channel in NuLi epithelia cell line
44
11 µm
3 µm
best concentration: 0.5 µM
normal human lung epithelia
CF patients lung epithelia
CF patients lung epithelia + AmB
Burke, M. D.; Cioffi, A. G.; Diaz, K. A.; Hou, J.; Grillo, A. U.S Patent WO2016073462, 2016
Strategy 2Synthetic anionphores
• Small molecule – drug like• Oral bioavailability• Self-organized to bind chloride selectively• Cell membrane permeability • Relatively effective formation and transport rate in
lipid bilayer• Measured by Ka and transporter:lipid ratio
45
Cholapod-based synthetic anionphores
46
OH
O
HOOH
OH
cholic acidY
O
ROX
X
McNally, B. A.; Koulov, A. V.; Lambert, T. N.; Smith, B. D.; Joos, J. B.; Sisson, A. L.; Clare, J. P.; Sgarlata, V.; Judd, L. W.; Magro, G.; Davis, A. P. Chem. Eur. J. 2008, 14, 9599-9606. Li, H.; Valkenier, H.; Judd, L. W.; Brotherhood, P. R.; Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.; Davis, A. P. Nature Chem., 2015, 8, 24-32.
X
NH
O
NH N
H
O
NH
NO2
NH
O
NH
CF3
NH
S
NH
NH
S
NH
NO2
NH
S
NH
CF3
YO
CH3O
O
CF3NH
SOO NH
NO2
H-bond donors
X
NH
O
NH N
H
O
NH
NO2
NH
O
NH
CF3
NH
S
NH
NH
S
NH
NO2
NH
S
NH
CF3
47
Y
O
ROX
X
Increase binding affinity
Increase binding affinity
YO
CH3O
O
CF3NH
SOO NH
NO2
Binding affinity vs. transport rate
48
Y
O
ROX
X
increase binding affinity
increase transport rate
SOO NH
NO2
O
CF3NH
O
CH3O
Y
Candidate of cholapod-based anionphores
49
Lipinski’s rule:Molecular weight: 500 logP < 5H-bond donors: 5H bond acceptors: 10
Molecular weight: > 700 logP = 8, too lipophilicH-bond donors: 5H bond acceptors: 10Ka > 1011 M-1 (first-order rate)Transporter:lipid ratio = 1:25000Slow movement across membrane
NH
O
H3COHN
HN
O
CF3
SS
HNHN
CF3
CF3
Li, H.; Valkenier, H.; Judd, L. W.; Brotherhood, P. R.; Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.; Davis, A. P. Nature Chem., 2015, 8, 24-32.
Decalin-based anionphores
NH HN
NH HN
XX
Ar Ar
O OR
X S, O
Ar
CF3F3C CF3 NO2
R -CH3 -C2H5 C8H17
50
Li, H.; Valkenier, H.; Judd, L. W.; Brotherhood, P. R.; Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.; Davis, A. P. Nature Chem., 2015, 8, 24-32.
Potential drug candidates
NH HN
NH HN
OO
O OC2H5
O2N NO2
51
Molecular weight: 569logP = 4.5H-bond donors: 5H bond acceptors: 12Ka > 6.8 x 102 M-1
(first-order rate)Excellent deliverability
Li, H.; Valkenier, H.; Judd, L. W.; Brotherhood, P. R.; Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.; Davis, A. P. Nature Chem., 2015, 8, 24-32.
NH------Cl distance:2.50 – 2.58 Å
Anionphore vs Forskolin
52
Delivery method: inhaled + co-taken with antibiotics to lungs of CF patients
Li, H.; Valkenier, H.; Judd, L. W.; Brotherhood, P. R.; Hussain, S.; Cooper, J. A.; Jurcek, O.; Sparkes, H. A.; Sheppard, D. N.; Davis, A. P. Nature Chem., 2015, 8, 24-32.
NH HN
NH HN
OO
O OC2H5
O2N NO2
1 +
1
Restoring CFTR chloride channel as CF treatment
ATP
ATP-powered pump100 – 103 ions/sActive transport
Ion channel107 – 108 ions/sPassive transport
Transporter102 – 104 ions/s
Marieb, E.N; Hoehn, K. Human anatomy and physiology; Pearson: New York, 2013. 53
NH HN
NH HN
OO
O OC2H5
O2N NO2
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
O O
OH NH2OH
Me
mycosamine
Chemical biology of ion transport
BackgroundViral transportBacterial transportEukaryotic transport
54
M2 channel Influenza A
EnterobactinE. coli
NH HN
NH HN
OO
O OC2H5
O2N NO2
O
OH
OH
OH
OMe
HO CO2H
HO
HO
OH
MeHO Me
O O
OH NH2OH
Me
mycosamine
AcknowledgementDr. John Frost
Dr. Karen DrathsDr. Xuefei Huang
Frost group:Yukari Nishizawa-Brennen
Kelly MillerSwetha Nisthala
55
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