Chemistry Tipping the Biological Seesaw
Sophie C. Royall & David J. Fox*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
Email: s.c.royall@warwick.ac.uk, d.j.fox@warwick.ac.uk
Thanks to Funxional Therapeutics Ltd and Dr D. J. Grainger
Inflammation is the bodies way of fighting invading foreign
microbes.
Macrophages – a type of white blood cell – are found
circulating the body in the blood. When they come across an
invading microbe they engulf and destroy it and send out a
message to recruit more white blood cells (macrophages,
neutrophils and monocytes) to the area so they can help fight
the infection and stop it spreading.
The result of this process is heat, redness, swelling and pain –
the physical properties of INFLAMMATION.
The sstr2 receptor is a bit like a seesaw – when
somatostatin is bound GH is affected but when BSCIs are
bound chemokines are affected.
somatostatin
The aim of my project is to synthesis a
catalogue of molecules analogous to
both somatostatin and BSCIs to
investigate the important part of the
molecules for tipping sstr2 from GH to
BSCI function..
BSCIs
sstr2 receptor
sstr2 receptor
GH regulated
chemokines regulated
somatostatin analogue
O
H2N
H2N
O
macrophage
HN
sstr2 receptor
sstr2 receptor
O
neutrophil
O
S
O
microbe is engulfed
microbe is destroyed
and messengers sent out
for more white blood cells
more white blood cells
INFLAMMATION
Chemokines are therefore a good target for anti-inflammatory
drugs – if chemokines are prevented from delivering their
message inflammation will be prevented.
monocyte
macrophage
neutrophil
macrophage releasing
chemokine messengers
increase in white blood
cells - INLFAMMATION
NO INFAMMATION
chemokine messengers stopped
Broad-Spectrum Chemokine Inhibitors (BSCIs) do just this.
O
O
N
O
S
O
N
O
S
O
HN
3
O
N
O
S
O
4
N
H2N
O
H2N
O
NH
O
5
HN
NH
O
HN
O
O
sstr2 receptor
O
HN
HN
O
O
HN
H
cells have receptors
on their surfaces
HN
O
O
8
N
O
S
O
HN
H
HN
HN
O
O
HN
H
HN
BSCI analogue
hybrid?
Cells send messages to each other via signalling
molecules. Receptors on the surfaces of the cells attach
to the signalling molecules for the message to be
conveyed.
7
O
O
O
HN
H
6
NH
NH
O
N
O
S
O
N
O
S
O
N
O
S
O
GH and chemokines regulated?
NH
NH
NH
The message is sent out by signalling molecules called
chemokines.
Sometimes inflammation is inappropriate and can
exacerbate certain diseases for example cancer, arthritis and
asthma.
HN
2
HN
1
NH
NH
O
chemokines
regulated?
GH regulated?
macrophage meets
invading microbe
NH
O
NH
O
monocyte
NH
NH
NH
message
messenger molecules bind
the receptors and convey the
message
Previously it was believed one signalling molecules would fit only one receptor to give a response – like a key (the
signalling molecule) fits only one lock (the receptor) and gives one response (the lock opens).
However it has been discovered the receptor can change shape to fit different signalling molecules to produce a
different response – like a hand fits around a pen and the response is to write, and it can also fit around a mug with
the response being to lift it to the mouth.
chemokine still able to bind
sstr2 blocked resulting in
inflammation being stopped
This is what is happened with BSCIs. They do not bind to the
chemokine receptor they bind to a receptor called sstr2 usually for a
signalling molecule called somatostatin. When somatostatin binds
sstr2 growth hormone (GH) is affected however when BSCIs bind
sstr2 chemokines are affected.
Chemistry Tipping the Biological Seesaw
Sophie C. Royall & David J. Fox*
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, U.K.
Email: s.c.royall@warwick.ac.uk, d.j.fox@warwick.ac.uk
Thanks to Funxional Therapeutics Ltd and Dr D. J. Grainger
The sstr2 receptor is a bit like a sesaw – when somatostatin is
bound GH is affected but when BSCIs are bound chemokines are
affected.
Inflammation is the bodies way of fighting invading foreign
microbes.
Macrophages – a type of white blood cell – are found circulating
the body in the blood. When they come across an invading
microbe they engulf and destroy it and send out a message to
recruit more white blood cells (macrophages , neutrophils and
monocytes) to the area so they can help fight the infection and
stop it spreading.
The result of this process is heat, redness, swelling and pain –
the physical properties of INFLAMMATION.
somatostatin
The aim of my project is to synthesis a
catalogue of molecules analogous to both
somatostatin and BSCIs to investigate the
important part of the molecules for each
function.
BSCIs
sstr2 receptor
sstr2 receptor
GH regulated
chemokines regulated
somatostatin analogue
O
H2N
H2N
O
macrophage
HN
O
neutrophil
macrophage meets
invading microbe
microbe is destroyed
and messengers sent out
for more white blood cells
microbe is engulfed
more white blood cells
INFLAMMATION
O
S
O
monocyte
macrophage
N
NO INFAMMATION
chemokine messengers stopped
Broad-Spectrum Chemokine Inhibitors (BSCIs) do just this.
O
N
O
S
O
N
O
S
O
4
N
H2N
O
O
NH
5
HN
NH
O
HN
O
O
O
HN
H
HN
HN
O
O
HN
7
HN
O
O
O
O
8
N
O
S
O
N
O
S
O
HN
H
NH
NH
O
O
O
GH and chemokines regulated?
6
N
O
S
O
N
O
S
O
sstr2 receptor
NH
NH
O
HN
H
HN
O
HN
H
HN
BSCI analogue
hybrid?
Cells send messages to each other via signalling molecules, there are receptors on the surfaces of the cells for the
signalling molecules to attach to and convey the signal.
cells have receptors
on their surfaces
increase in white blood
cells - INLFAMMATION
O
S
O
NH
neutrophil
macrophage releasing
chemokine messengers
O
O
HN
3
chemokines regulated?
GH regulated?
The message is sent out by signalling molecules called
chemokines.
Chemokines are therefore a good target for antiinflammatory drugs – if chemokines are prevented from
delivering their message inflammation will be prevented .
HN
2
HN
1
NH
NH
O
sstr2 receptor
sstr2 receptor
H2N
Sometimes inflammation is inappropriate and can
exacerbate certain diseases for example cancer, arthritis and
asthma.
NH
O
NH
O
monocyte
NH
NH
NH
message
messenger molecules bind
the receptors and convey the
message
Previously it was believed one signalling molecules would fit only one receptor to give a response – like a key (the
signalling molecule) fits only one lock (the receptor) and gives a response (the lock opens).
However it has been discovered the receptor can change shape to fit different signalling molecules to produce a
different response – like a hand fits around a pen and the response is to write, and it can also fit around a mug with the
response being to lift it to the mouth
chemokine receptor blocked
so chemokines can't bind
so inflammation is stopped
chemokine still able to bind
sstr2 blocked resulting in
inflammation being stopped