Peptide and Protein Drugs Therapeutic applications, structure, stability

Proteins have the most dynamic and diverse role of any macromolecule in the body Catalysing biochemical reactions, Forming receptors and channels in membranes, Providing intracellular and extracellular scaffolding support, Transporting molecules within a cell or from one organ to another. There are 25,000–40,000 different genes in the human genome, and with alternative splicing of genes and post-translational modification of proteins (for example, by cleavage, phosphorylation, acylation and glycosylation), the number of functionally distinct proteins is likely to be much higher ! Involved in disease conditions

Advantages of Protein Therapeutics Over Small Mol Wt Drugs 1. Proteins serve a highly specific and complex set of functions that cannot be mimicked by simple chemical compounds. 2. There is often less potential for protein therapeutics to interfere with normal biological processes and cause adverse effects. 3. As the body naturally produces many of the proteins, these agents are often well tolerated with less immune responses. 4. Fourth, for diseases in which a gene is mutated or deleted, protein therapeutics can provide effective replacement treatment without the need for gene therapy 5. The clinical development and FDA approval time of protein therapeutics may be faster than that of small-molecule drugs. ! Patents

Classification of therapeutic proteins according to their pharmacological function Group 1 : Enzymes and regulatory proteins Group Ia: to replace a particular activity in cases of protein deficiency or abnormal protein production. Examples; lactase in patients lacking this gastrointestinal enzyme, replacing vital blood-clotting factors such as factor VIII and factor IX in haemophiliacs. Insulin for the treatment of diabetes. Patients with cystic fibrosis are often treated with a combination of pancreatic enzymes such as lipases, amylases and proteases .Diseases caused by metabolic enzyme deficiencies, such as Gaucher’s disease, mucopolysaccharidosis, Fabry disease

Group 1b: enhance the magnitude or timing of a particular normal protein activity Examples: recombinant erythropoietin in cases of chemotherapy induced anaemia it is used to increase erythrocyte production, renal failure. Neutropaenic patients with granulocyte-colony stimulating factor (G-CSF) which stimulate an increase in the number of neutrophils. In IVF procedures, FSH, hCG Life saving effects on thrombosis and haemostasis. Alteplase (recombinant tissue plasminogen activator (tPA), is used in blood clots in conditions as coronary artery occlusion, acute ischaemic stroke and pulmonary embolism It cleaves plasminogen to plasmin, which then degrades fibrin and thereby lyses fibrin-based clots Supra-physiological levels of coagulation factor VIIa may catalyse thrombosis and stop life-threatening bleeding in patients with haemophilia A or B Immunomodulators

Group 1c: foreign proteins with novel functions and endogenous proteins that act at a novel time or place in the body Examples: Papain, a protease, to degrade proteinaceous debris in wounds. Collagenase. Recombinant human deoxyribonuclease I (DNASE1), neutrophils DNA and cystic fiborosis

Group II: targeted proteins: The exquisite binding specificity of monoclonal antibodies and immunoadhesins Group IIa use the antigen recognition sites of immunoglobulin (Ig) molecules or the receptor-binding domains of native protein ligands to guide the immune system to destroy specifically targeted molecules or cells. Mostly for inflammatory disease situations, tumour necrosis factor (TNF) receptor and the Fc region of the human antibody protein IgG1 (inflammatory arithritis, psoriasis) Anti-infectives, viral infections Oncology, rituximab is a human/mouse chimeric monoclonal antibody that binds to CD20, a transmembrane protein expressed on >90% of B‑cell non-Hodgkin’s lymphomas, and targets the cells for destruction by the body’s immune system

Group IIb: selective delivery of small-molecule drugs and proteins to the intended therapeutic target. Examples: gemtuzumab ozogamicin, links the binding region of a monoclonal antibody directed against CD33 with calicheamicin, ibritumomab tiuxetan, a monoclonal antibody that is directed against CD20 and linked to a radioactive yttrium isotope Delivery of proteins and other macromolecules to the CNS, which is challenging owing to the highly selective blood–brain barrier (BBB).

Group III : protein vaccines: prophylactic or therapeutic vaccines Group IIIa are used to generate protection against infectious diseases or toxins. A successful example is the hepatitis B vaccine Group IIIb: therapeutic anticancer vaccines: B‑cell non-Hodgkin’s lymphoma

Group IV : protein diagnostics Examples: purified protein derivative (PPD) test, which determines whether an individual has been exposed to antigens from Mycobacterium tuberculosis. Imaging agents: Caromab pendetide is an indium‑111-labelled anti-PSA (prostate specific antigen) antibody that can be used to detect prostate cancer