advances-in-protein-chemistry

New Peptide Based
Therapeutic Approaches
Riyasat Ali 1 *, Richa Rani 2 and Sudhir Kumar 3
1
Department of Biochemistry, All India Institute of Medical Sciences,
New Delhi 110029, India
2Department of Biotechnology, Indian Institute of Technology,
Roorkee 247667, Uttarakhand, India
3
Department of Environmental Health, College of Medicine,
University of Cincinnati, Cincinnati, OH 45267-0056, USA
*Corresponding author: Riyasat Ali, Department of Biochemistry,
All India Institute of Medical Sciences, New Delhi 110029, India,
E-mail: riyasataiims@gmail.com
Abstract
A large number of chemically well defined and synthetic linear as well as branched therapeutics peptides have been developed and
used for a large number of therapeutic applications. Peptides and peptide analogues have been developed to mimic naturally occurring
molecules like hormones; growth factors etc. along with recently developed several peptide inhibitors. Moreover, large numbers of
studies have been performed to establish peptides as an immune prophylactic and immune diagnostic for several infectious diseases
like malaria, HIV and plague etc. Synthetic peptide approach have been popularised due to its ease of synthesising large amount of
peptides and liberty to modify peptides in order to make them more effective. In the last couple of decades, with the advancement of
technology, it has become easy to synthesise longer peptides using peptide conjugation and modification strategies. Moreover, wide
range of targeted delivery vehicles of peptides using several bio-compatible polymers have been developed which made peptide drug
approach more popular for therapeutic purposes. Targeted and drug release kinetics for optimum drug dispensing have been greatly
advanced which increases bio-availability and stability of peptides in the system for longer therapeutic effects.
Introduction
The enormous increase in the cost and time span to develop a conventional drugs led researchers and pharmaceutical companies
to develop new cost-effective products based of synthetic peptide strategy, which led us to develop large number of peptides of
medical importance. Although, peptides are generally considered to be poor drug candidates because of their low oral bioavailability
and propensity to be rapidly metabolized, yet development of synthetic single and/or linear peptides was found to be a remarkable
advancement for drug discovery and therapeutics. In the past, a large number of potent peptide drugs have been developed as
chemically defined or recombinant peptides. Although peptides have several advantages over small molecules and antibodies, there
are some limitations associated with peptides which limit their use as a mainstream drug source. Firstly, they exhibit low potency and
short half life, owing to rapid renal clearance, and lack in vivo stability due to protease degradation. Secondly, peptides also exhibit
limited access to the intracellular space and can contain potential immunogenic sequences (random peptides) in general. Therapeutic
peptides traditionally have been derived from three sources: (i) natural or bioactive peptides produced by plants, animal or human
(derived from naturally occurring peptide hormones or from fragments of larger proteins); (ii) peptides isolated from genetic or
recombinant libraries and (iii) peptides discovered from chemical libraries.
With the advancement of peptide synthesis technologies, improved productivity and reduced metabolism of peptides, along
with alternative routes of administration, several bioactive peptides have been developed which are found to be highly functional
with many serving as potent agonists and antagonists against several receptors involved in disease progression. Therapeutic peptides
contribute significantly to the treatment of diabetic, osteoporotic, oncologic, gastroenterologic, cardiovascular, immunosuppression,
acromegaly, enuresis, antiviral, obesity, antibacterial and antifungal indications (Table 1). On the other hand, a large number of
immuno-prophylactic and immuno-diagnostic peptides have also been developed for several infectious diseases like HIV, Malaria,
plague, influenza, anthrax and autoimmune diseases like Type 1 Diabetes etc. Although, there is an immense development in the
field of peptide chemistry yet it has been associated with many difficulties which are related to the stability of peptides in the system,
structure and sometimes immunogenicity of long peptides, that we are not interested. To use peptide as a therapeutic peptide, its
biological activity, pharmacokinetic profile and low immunogenicity are crucial parameters. Various chemical modifications have
been employed to overcome these limitations of peptides. Many cyclic peptides, pseudo-peptides (modification of the peptide bond)
and peptidomimetics (non-peptide molecules) preserving the biological properties of peptides have been developed to increase their
stability and bioavailability. However, targeted delivery of therapeutic peptides is still a challenging task. Many therapeutic peptides
and peptide analogues do not have ideal delivery and release kinetics and hence new delivery system need to be developed which can
ideally suited pharmacokinetics, bioavailability and toxicity profiles as well. In addition, peptide delivery profile/efficacy has been
developed taking various pharmacokinetic parameters like extended release, pulsatile delivery, increased bioavailability and renal
clearance. Furthermore, various routes of delivery (transdermal, pulmonary, nasal and oral) of peptide have been developed recently.
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