Peptides & Proteins as Therapeutics

The most frequently used peptide/protein drugs can be classified in three main groups.
Group I includes exogenously administered protein drugs in case of a deficiency. Insulin
for Type I diabetes, growth hormones for treatment of growth factor deficiency in children,
Protein C supplements for prevention of venal thrombosis or blood clotting factors in case
of haemophilia are few examples. Group II consists of monoclonal-antibody-based drugs
for autoimmune diseases such as allergy, arthritis and even for certain cancers. This
group actively binds and manipulates a molecule or an organism that is the cause of
malfunction or disease. Monoclonal antibodies that target and neutralize the effects of
tumor necrosis factor (TNF) have been successful for treatment of rheumatoid arthritis
and inflammatory bowel syndrome. Rituximab and cetuximab are important antibody
treatments in lymphoma and colorectal cancer respectively. While the former binds to an
over-expressed transmembrane protein on cancer cells and facilitates their destruction
by the immune system, the latter targets epidermal growth factor of affected cells to
impede their growth and proliferation. Group III includes vaccines as a preventative way
to overcome infectious diseases. Hepatitis B vaccine significantly protects those who are
administered with a non-infectious protein of hepatitis B surface antigen. A approved
vaccine against human papillomavirus (HPV) is shown to prevent not only genial warts,
but also certain cervical cancers. Another example is the anti-Rhesus D antigen that is a
long-used vaccine for desensitization of Rh-negative mothers towards Rh-positive fetus,
in order to prevent immune reactions and miscarriages in subsequent pregnancies.

Currently, over 200 biopharmaceuticals that include peptide, protein and antibody-based
drugs are in use in clinic. Within these molecules, therapeutic peptides with <50 amino
acids make up more than 60 brand-name drugs. Some of these are antidiabetic peptides
such as amylin, exentide and liraglutide for treatment of Type I and/or Type II diabetes,
angiotensin converting enzyme (ACE) inhibitors for treatment of hypertension, anti-HIV
peptides against AIDS infection, calcitonins for treatment of postmenopausal
osteoporosis and Paget’s disease, central nervous system (CNS) agents to manage
severe chronic pain, gonadotropin releasing hormone derivatives for treatment of
advanced forms of prostate cancer and breast cancer, oxytocin for initiation of uterine
contractions and prevention of postpartum haemorrhage, somatastatin analogues for
treatment of acromegaly and carcinoid tumors and vasopressin analogues for diabetes
insipidus. In addition, some peptides are used solely for diagnostic purposes such as,
secretins (for pancreatic dysfunction) and adrenocorticotropic hormone derivatives (for
detection of adrenocortical insufficiency).

Advantages of Peptide Drugs over Small Molecules and

Other Biopharmaceuticals

Compared to higher molecular weight biopharmaceuticals (protein and antibody drugs),

peptides have more potential to be modified and mutated without compromising their
activity. Owing to their small size, penetration at the target site can be obtained when
proper modifications are done. Manufacturing small peptides are more affordable than
synthesis of larger proteins or production of monoclonal antibodies, and the shelf-life of
peptides is generally longer.

Peptide drugs carry even superior advantages over small organic compounds. First, they
can target a larger interface on a protein/enzyme that leads to better specificity, efficacy
and selectivity. Most peptide drugs are receptor agonists and are derived from natural
ligands of the target receptor. Because of the exclusive interactions of the peptide drugs
with their target receptors/proteins, they do not display cross-reactivity, thus minimizing
the side effect. In addition, they are less likely to elicit an immune response since they
are derived from naturally occurring peptides of the body. Moreover, small amounts of
the peptides suffice for activation of their receptors, which reduces the dosage of the
drug. Although proteolysis is a big problem for small peptides, their degradation by-
products are just small peptide fragments or amino acids and are not toxic. Clearance of
these molecules is easily done without any damage or accumulation in organs.

Reference:

Diren Pamuk, Design and engineering of new glucagonlike-peptide-1 analogues