Download Proteins as drugs

Proteins as drug targets
• Types of proteins with which drug interact are.
Eg.
1. Carrier/transport Proteins
2. Structural Proteins
3. Receptors
4. enzymes
5. Peptides
6. Monoclonal antibodies
Carrier/transport Proteins
• Are present in the cell membrane and act as cell’s smugglers-smuggling
important chemical building blocks of amino acids, sugars and nucleic acids
across the cell membrane such that the cell can synthesize its proteins,
carbohydrates and nucleic acids.
• Amino acids, sugars are polar molecules they can not traverse the cell
membrane freely hence transport proteins have binding site to bind with polar
molecules and can easily encapsulate them and transport them inside the cell.
• There are specific transport proteins for the different molecules that needs to
be smuggled across the membrane. The binding site of these transport
proteins vary in structure such that they can recognize and bind their specific
guests.
Carrier/transport Proteins
• There are several important drugs which targets transport proteins.
• These drugs fools the transport proteins into thinking that they are the usual
guest molecules. The transport protein accepts drug and carries it across the
membrane, delivering the drug into the cell. This is one way of delivering
highly polar drugs into cell or across cell membrane.
Eg. The anticancer agents methotrexate and antibiotic erythromycin are
absorbed better than expected because of active transport by carrier
proteins.
• In some cases, drugs are tightly bound to the carrier proteins once they are
wrapped up and remains as permanent lodgers. Carrier protein is then no
longer able to be carry its usual guest across the cell membrane. EG.
Antidepressant drug fluoxetine acts in this way. It remains permanently
attached to carrier protein and inhibits the carrier protein responsible for
the uptake of serotonin.
• Note: serotonin is responsible for regulation of mood. Modulation of
serotonin at synapses is thought to be a major action of several classes of
pharmacological antidepressants.
Fluoxetine
serotonin
Structural Proteins
• Structural proteins do not normally act as drug targets.
• However, the structural protein tubulin is exception.
• Tubulin molecules polymerizes to form small tubes called microtubules in cell
cytoplasm. This microtubules are responsible for maintenance of shape,
exocytosis and release of neurotransmitters.
Structural Proteins
• They are also involved in mobility of cells. This property of microtubules
is used for the designing some drugs.
Eg. In arthritis inflammatory neutrophils (which normally protects body
against infections) can enter joints and causes pain. This disease can be
treated by administering colchicine which binds to tubulin and causes
microtubules to depolarize. Once the microtubules have been broken
down, the neutrophils lose their mobility and can no longer migrate into
the joints.
Colchicine
Structural Proteins
• Tubulin is also very crucial for cell division. When the cell is about to divide,
its microtubules depolymerize to give tubulin. The tubulin then
repolymerizes to form a spindle which leads to division in two cells.
• Several important anticancer drugs work by binding tubulin to prevent
polymerization and thus inhibits growth of tumors.
• Eg. Vincristine prevent polymerization of tubulin to form spindle, whereas
paclitaxel stimulates the formation of microtubules and thus prevents
depolymerization.
Vincristine
Paclitaxel
Antibodies
• Another important group of proteins which are present in the body are Antibodies.
• Antibodies are crucial to the recognition and destruction of foreign cells by the immune
response.
• Specific antibodies binds to specific antigens on cells. All cells have antigens on their
outer surface. They acts as molecular signatures for different cells allowing antibodies to
distinguish between body’s own cells and foreign cells.
• Since antibodies can recognize the chemical signature of a particular cell, they have great
potential in targeting drugs to specific cells in the body.
• Antibodies which can recognize a particular human cell is generated by exposing another
organisms to that cell. The drug can be attached to such antibodies and the it will be
carried to target cell by the antibody.
• Eg. The first antibody to be used clinically was specific for an antigen on lymphocytes. The
antibody was used to tag lymphocytes which had turned cancerous and encouraged the
body to destroy them.
Peptides
• Many of bodies important hormones are peptides, and in certain
cases body fails to produce sufficient quantities. Therefore, it is
useful to provide such peptides or hormones as drugs to make up for
the deficiency.
• Several such enzymes have been introduced in market eg. Insulin,
human growth hormone.
Enzymes and Receptors
• The most imortant drug targets in medicinal chemistry are enzymes
and receptors and will be discussed in detail separately.
Proteomics
• A lot of publicity has been rightly accorded to the Human Genome Project
called genomics and it involves the identifi cation of the genetic code in
humans and other species.
• The success of this work has been hailed as a breakthrough that will lead
to a new era in medicinal research.
• DNA is the blueprint for the synthesis of proteins and so the task is now to
identify all the proteins present in each cell of the body and, more
importantly, how they interact with each other—an area of science known
as proteomics.
• Proteomics is the study of the structure and function of novel proteins
discovered through genomics.
• Thus Proteomics involves analysis of the structure and function of
proteins, many of which are completely new to science, and to see
whether they can act as novel drug targets for the future.
Challenges in proteomics
• Proteomics is far more challenging than genomics because of the complexity of
interactions that can take place between proteins.
• the pattern and function of proteins present in a cell depend on the type of cell it
is and this pattern can alter in the diseased state.
• it is not possible to simply derive the structure of proteins based on the known
gene sequences. This is because different proteins can be derived from a single
gene and proteins are often modified following their synthesis.
• There are roughly 40,000 genes, whereas a typical cell contains hundreds of
thousands of different proteins.
• knowing the structure of a protein does not necessarily suggest its function or
interactions.
Process for identification of proteins
• Identifying the proteins present in a cell usually involves analyzing
the contents of the cell and separating out the proteins using a twodimensional gel electrophoresis.
• Mass spectrometry can then be used to study the molecular weight
of each protein.
• Then the Primary structure can be identified by traditional
sequencing techniques.
• The secondary and tertiary structures can be crystallized and
determine its structure by X-ray crystallography(but Not all proteins
can be crystallized)
• In recent years nuclear magnetic resonance (NMR) spectroscopy has
been successful in identifying the tertiary structure of some proteins.
Identification of role of protein
• There then comes the problem of identifying what role the protein
has in the cell and whether it would serve as a useful drug target.
• If it does show promise as a target, the final problem is to discover or
design a drug that will interact with it.
THANK YOU
-PHARMA STREET