Pharmacology of Proteins & Peptides can be summarized as follows: 1. Peptides are short chains of amino acids linked by peptide bonds, while proteins are longer chains. There is an arbitrary dividing line of 50 amino acids to distinguish peptides from proteins. 2. Peptide mediators include neurotransmitters, hormones, growth factors, and cytokines that regulate various physiological processes through immunological, inflammatory, and reparative responses. 3. Cytokines are peptide mediators that include interleukins, interferons, tumor necrosis factor, and colony stimulating factors. They play important roles in innate immunity, lymphocyte differentiation, inflammation, and hematopoiesis.

1. Pharmacology
of
Proteins & Peptides

2. Terminology
Peptides (from Gr. "digested")  short chains of amino acid
monomers linked by peptide (amide) bonds, the covalent chemical
bonds formed when the carboxyl group of one amino acid reacts with
the amino group of another.
Polypeptide  long, continuous, and unbranched peptide chain

3. Protein and peptide mediators  3 to 200 residues
Difference between peptides and proteins  arbitrary dividing
line of 50 amino acid residues

4. Peptide mediators :
1. Neurotransmitters and neuroendocrine mediators
2. Hormones from non-neural sources:
a) Plasma-derived peptides, notably angiotensin and bradykinin,
b) substances such as insulin, endothelin, atrial natriuretic peptide and leptin
3. Growth factors: produced by many different cells and tissues that
control cell growth and differentiation
4. Mediators of the immune system (cytokines and chemokines)

5. cytokines

6. DEFINITION: Peptide mediators or intercellular messengers
that regulate immunological, inflammatory and reparative
host responses.
Highly potent
Includes
Interleukins Interferons
Tumor necrosis factor Colony
stimulating factor Others

7. Innate immunity:IL-1,IL-6,TNF,type-1 Interferon.
Regulate differentiation of lymphocytes:
IL-2:T cells
IL-4:TH-2 and B-cells IL-12:TH-1
IL-15:NK cells.
Activate inflammatory cells:IFN-gamma,IL-5, TNF
Stimulate haematopoiesis: CSFs.
Affect leucocyte movement: chemokines.

11. TYPES:
Alpha: leucocytes
Beta: fibroblasts
Gamma: T-lymphocytes. immunomodulatory, anti
proliferative.
Biological effects: Anti viral
Anti bacterial
Immunoregulatory
Inhibits cell growth and proliferation

12. USES:
IFN-alpha: Hairy cell leukemia
CML, Malignant melanoma kaposi sarcoma,
RCC, carcinoid Hepatitis Band C infections
IFN beta: Multiple sclerosis(relapsing type)
IFN gamma: Chronic granulomatous diseases
Recombinant IFN-γ has been shown to reduce the frequency
of infections markedly in patients with chronic
granulomatous disease.
Local application of high doses-URTI, genital warts and
herpetic keratitis.

13. Serum factor found to induce haemorrhagic necrosis in
certain tumors.
TYPES: TNF-αlpha(cachectin)
TNF-beta Lymphotoxin-α (LT-α)
Other members of the TNF family include Fas ligand (FasL),
receptor activator of NF-κB ligand (RANKL), CD40 ligand
(CD40L) and TNF-related apoptosis inducing ligand (TRAIL).
TNF, IL-1, and IL-6 (as well as some other proinflammatory
cytokines) can activate the extrinsic pathway of coagulation, in
part by promoting expression of tissue factor (TF), on
endothelial cells and monocytes.

14. Anti TNF α MONOCLONAL ANTIBODIES.
ADALIMUMAB: rheumatoid arthritis
ETANERCEPT: Rheumatoid arthritis
Psoriatic arthritis juvenile RA
INFLIXIMAB: Crohn’s disease
Ulcerative colitis Ankylosing
spondylitis Psoriatic arthritis
IL-1 receptor antagonist - ANAKINRA

15. C-X-C(alpha-chemokines): acts on
Neutrophils.
IL-8.
Inducers: microbial products,IL-1,TNF.
C-C(beta-chemokines):
MCP-1(monocyte chemo attractant protein) Eotaxin
MIP-1alpha(macrophage inflammatory protein) RANTES
C(gamma- chemokines): lymphotacin
CX3C: fractalkine

16. GM-CSF is a hematopoietic growth factor and proinflammatory
cytokine produced by multiple cell types, including bronchial
epithelial cells, monocytes, and endothelial cells.
As a growth factor, GM-CSF promotes an increase in the number of
circulating polymorphonuclear nuclear cells
(PMNs).
Crohn’s disease may result, at least in part, from impaired innate
immunity (e.g., caused by a mutation in the NOD2 gene),
recombinant GM- CSF might be a therapeutic option for this
condition.

17. Proteins
and
peptides as drugs

18. Many of the proteins currently in therapeutic use  functional human
proteins prepared by recombinant technology, which are used to
supplement the action of endogenous mediators.
1. Insulin
2. Growth hormone
3. ACTH
4. Erythopoetin
5. GM-CSF

19. Despite the large number of known peptide mediators, only a few peptides, mostly close
analogues of endogenous mediators, are currently useful as drugs.
In most cases, peptides make poor drugs,because:
 - They are poorly absorbed when given orally
 - They have a short duration of action because of rapid degradation in vivo
 - They do not predictably cross the blood-brain barrier
 - They are expensive and difficult to manufacture
 - They may be immunogenic.
Smaller peptides are used therapeutically mainly when there is simply no viablealternative

20. Peptide antagonists

21. The most important peptide receptor antagonists in clinical use :-
 Naloxone, Naltrexone (μ-opioid receptors): used to antagonise opiate
effects
 Losartan, Valsartan, etc. (angiotensin AT1 receptors)
 Bosentan (endothelin ET1/ET2 receptors)
 Atosiban (Oxytocin antagonist)
 Aprepitant (substance P antagonist)
 Ganirelix, Cetrorelix etc (GnRH antagonists)

22. Thank you