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NOVEL TARGET SITES AND DRUG DELIVERY SYSTEMS: A REVIEW
Mathew George, Lincy Joseph, Nimisha M Paul*
Pushpagiri College of Pharmacy, Thiruvalla-689107, Kerala, India
*corresponding author, address: Mattappillil house, Pipeline junction, Kerala, Kochi-682022.
contact number: +919400877216, e mail id:[email protected]
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ABSTRACT
The present review gives information regarding the novel target sites as well as drug delivery
methods. The aim of Novel Drug Delivery System is to provide a therapeutic amount of drug
to the appropriate site in the body to accomplish promptly and then maintain the desired drug
concentration. The ultimate goal of drug delivery research is to help patients by developing
clinically useful formulations. Novel therapeutics are applicable in areas with a high unmet
medical need are based on innovative drug targets. Although ‘biologicals’ have increased the
space for druggable molecules, the number of appropriate drug targets is still limited.
Discovering and evaluating the potential therapeutic benefit of a drug target is based upon not
only on experimental, mechanistic and pharmacological studies but also on a theoretical
molecular modelling, druggability assessment, an early evaluation of potential side effects and
considerations regarding opportunities for commercialization. The discovery and exploitation
of new drug targets is a key focus for both the pharmaceutical industry and as well for
academic biomedical research.
KEYWORDS : novel drug, druggable, delivery system, biologicals, drug target
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Introduction
Understanding the identity of drug targets that are encoded by the human genome is of great
importance for the development of new pharmaceutical products and the allocation of
resources within academic and industrial biomedical research. Currently used marketed drugs
mediate their effects through only a small number of the potential human target proteins.
Recent analyses of discontinued drug development procedures, novel drug products and
clinical trial failures point to the fact that an increasing number of compounds do not meet the
efficacy endpoints. The success rates for new development projects in Phase II clinical trials
have fallen from 28% (2006–2007) to 18% (2008–2009).The goal of any drug delivery
system is to provide a therapeutic amount of drug to the proper site in the body and then
maintain the desired drug concentration. A well designed controlled drug delivery system can
overcome some of problems of conventional therapy and enhance therapeutic efficacy of the
given drug. During the last several decades controlled drug delivery technology has advanced
significantly, leading to the development of various clinical formulations improving patient
compliance and convenience.
The advent of data-rich high-throughput functional screening methods has led to the
discovery of small molecules with novel modes of action. Application of these screening
techniques has enabled the detection of numerous types of molecules including those
classified as ‘allosteric modulators’. Alone, these molecules can have no intrinsic activity on
their target – instead, they modulate the activity of the target when the endogenous ligand for
the target is bound. There is a long history of the study of allosteric modulation of certain
classes of proteins, for example, enzymes; however, the development of highthroughput
functional assays has enabled the discovery of allosteric modulators for other classes of
protein targets of high interest to the pharmaceutical industry and is a more recent
phenomenon.
A ‘druggable’ target is a protein, peptide or nucleic acid with intrinsic activity that can be
modulated by a drug, which consist of a small molecular weight chemical compound
(SMOL) or a biologic (BIOL), such as an antibody or a recombinant protein.
Recent developments
Allosteric modulators- Novel Drug Class
GPCRs are the largest family of integral membrane receptors, and account for 3-4% of the
human genome. They have explored to recognise a wide range of endogenous stimuli, and
function by transmitting messages from the exterior to the interior of the cell. Activation of
GPCRs by their endogenous ligand shifts the conformation of the receptor from an inactive to
an activated state, activating the G-protein associated with the receptor and initiating
intracellular signalling cascades that mediate cellular responses. The ubiquitous distribution
of GPCRs and their involvement in all physiological processes make them extremely
attractive targets for drug development.
Allosteric modulators are a novel class of small molecule drug candidates with a chemical
structure unrelated to that of competitive agonist or antagonist drugs, and as such represent
first-in-class drugcandidates with a high potential as a druggable molecule. These compounds
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aretypically drug-like and amenable to chemical optimisation for oralbioavailability and
favourable pharmacokinetic properties. Example: ADX47273 is an illustration of the
potential for the discovery and development of allosteric modulator. It is a novel positive
allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Used
fortreatment of central nervous system diseases, including schizophrenia and cognitive
dysfunction.
Ribosomes as antibiotic targets
Ribosomes are essential for protein synthesis in all cells. Ribosomes have many
evolutionarily conserved features but important structural differences exist between
bacterialand eukaryotic ribosomes. Ribosome structural differences between organisms can
be exploited as potential targets in drug development. Many clinically useful antibiotics exert
their antimicrobial effects by blocking protein synthesis on the bacterial ribosome. The
structure of the ribosome has recently been determined by X-ray crystallography, revealing
the molecular details of the antibiotic-binding sites. The crystal data explain many earlier
biochemical and genetic observations, including how drugs exercise their inhibitory effects,
how some drugs in combination enhance or impede each other's binding, and how alterations
to ribosomal components confer resistance. The crystal structures also provide insight as to
how existing drugs might be derivatized (or novel drugs created) to improve binding and
circumvent resistance.
Magnetised carrier as novel drug delivery system
Magnetism play an important role in different applications of health care, magnetic particles
composed of magnetite which are well tolerated by the body. Magnetic nanoparticles usually
exist or can be prepared in the form of single domain or superparamagnetic magnetite
(Fe3o4), greigite (Fe3s4), magnemite (r-Fe2o3), iron, nickel, etc. synthetic magnetic
materials have many applications in optics, electronic& energy storage. Magnetism have
application in numerous field like diagnostics, drug targeting, molecular biology, cell
isolation, cell purification, hyperthermia, radioimmunoassay.
Magnetic drug delivery by particulate carriers is a very efficient method of delivering a drug
to localized disease site. Very high concentrations of chemotherapeutic or radiological agents
can be achieved near the target site,such as tumour, without any toxic effects to normal
surrounding tissue or to whole body. In magnetic targeting, a drug or therapeutic radioisotope
is bound to a magnetic compound, injected into patient’s blood stream, and then stopped with
a powerful magnetic field in the target area. Depending on the type of drug, it is then slowly
released from the magnetic carriers (e.g. release of chemotherapeutic drugs from magnetic
microspheres) or confers a local effect. It is thus possible to place large amounts of drug
targeted magnetically to localized disease sites.
Mitogen activated protein kinase (MAPK) cascade- a novel drug target against fungal
pathogens
It is seen that mitogen activated protein kinase (MAPK) cascade transmits signals from outer
cell surface to the nucleus and is involved in fungal survival mechanisms against
environmental stress conditions. MAPK cascade molecules can be good targets of antifungal
drugs to avoid fungal survival against conventional drugs.Resistance to antibiotics in
pathogenic fungi is a problem of special importance in recent time. Though bacterial drug
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resistance has been studied over for the last few decades, such studies for pathogenic fungi
have got recent interest. Treatment with antifungal drugs often results in the appearance of
resistant strains of fungi. Different signal transduction mechanisms are important for fungi
inenvironmental sensing and survival that directly or indirectlylead to drug resistance or
reduction of stress exerted by antifungal drugs. MAPK signalling cascade that transmits
signals from outer cell surface to the nucleus has known to be one of the major players in
such processes. The role of MAPK cascade in fungi is very central which predicts the MAPK
molecules potential drug targets.
Cytochrome P450: novel drug target against multidrug resistant bacteria
Novel drug strategies are needed to combat the global threat posed by multidrug-resistant
strains of Mycobacterium tuberculosis (Mtb). The genome sequence of Mtb has revealed an
unprecedented number of cytochrome P450 enzymes in a prokaryote, suggesting fundamental
physiological roles for many of these enzymes. Several azole drugs (known inhibitors of
cytochromes P450) have been shown to have potent anti-mycobacterial activity, and the most
effective azoles have extremely tight binding constants for one of the Mtb P450s (CYP121).
The structure of CYP121 has been determined at atomic resolution, revealing novel features
of P450 structure, including mixed haem conformations and putative proton-relay pathways
from protein surface to haem iron. The structure provides both a platform for investigation of
structure and mechanism of cytochrome P450, and for design of inhibitor molecules as novel
anti-tubercular agents.
Chronotherapy: a novel drug delivery method
Chronotherapy refers to the use of circadian, ultradian, infradian & seasonal or other
rhythmic cycles in the application of therapy. There are number of conditions which show a
circadian pattern and advantage could be taken by timing and adjusting the administration of
drugs according to the circadian rhythm of the disease. Some of the conditions, which may be
significantly benefited, are hypertension, myocardial infarction, bronchial asthma, peptic
ulcer, arthritis, duodenal ulcer, diabetes, neurological disorder, cancer and
hypercholesterolemia. Chronotherapy can be classified into time controlled systems wherein
the drug release is controlled primarily by the delivery system, stimuli induced in which
release is controlled by the stimuli, such as the pH or enzymes present in the intestinal tract or
enzymes present in the drug delivery system and externally regulated system where release is
programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation.
Heat shock proteins and cancer: a novel therapeutic agent
Heat shock proteins (HSPs) are an evolutionary conserved family of proteins whose
expression increases in response to a variety of different metabolic insults. Despite their
designation, most of the HSPs are constitutively expressed and perform essential functions.
Until recently, heat shock proteins (also known as heat stress proteins) have mostly been
regarded as intracellular molecules that mediate a range of essential housekeeping and
cytoprotective functions. However, interest in their role as intercellular signalling molecules
has been fuelled by the observations that these molecules can be released and are present in
the extracellular environment under physiological conditions. They can elicit cytokine
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production by, and adhesion molecule expression of, a range of cell types, and they can
deliver maturation signals and peptides to antigen presenting cells through receptor-mediated
interactions. These functions suggest that heat shock proteins could be immunoregulatory
agents with potent and widely-applicable therapeutic uses. Furthermore, the induction of selfheat shock protein immune reactivity can attenuate autoimmunity and delay transplant
rejection, and heat shock proteins derived from tumours and pathogens can elicit specific,
protective immunity. This review will focus on this rapidly evolving area of heat shock
protein biology.
Microspheres: a novel drug delivery system
Microspheres are characteristically free flowing powders consisting of proteins or synthetic
polymers which are biodegradable in nature and ideally having a particle size less than
200μm. A well designed controlled drug delivery system can overcome some of the problems
of conventional therapy and enhance the therapeutic efficacy of a given drug. There are
various approaches in delivering a therapeutic substance to the target site in a sustained
controlled release fashion. One such approach is using microspheres as carriers for drugs. It is
the reliable means to deliver the drug to the target site with specificity, if modified, and to
maintain the desired concentration at the site of interest without untoward effects.
Microspheres received much attention not only for prolonged release, but also for targeting of
anticancer drugs to the tumour. In future by combining various other strategies, microspheres
will find the central place in novel drug delivery, particularly in diseased cell sorting,
diagnostics, gene & genetic materials, safe, targeted and effective in vivo delivery and
supplements as miniature versions of diseased organ and tissues in the body.
Nanoparticles for cancer drug delivery
The emergence of nanotechnology has made a significant role on clinical therapeutics in the
last few decades. Advances in nanoscale drug carriers such as liposomes and polymeric
nanoparticles have enabled more efficient and safer drugs. Advantage of nanoparticle drug
delivery, include longer circulation half- lives, improved pharmacokinetics and reduced side
effects.
Nanoparticles have the advantage of targeting cancer by being accumulated and entrapped in
tumours (passive targeting). The phenomena are called the enhanced permeation and
retention effect, caused by leaky angiogenetic vessels and poor lymphatic drainage and has
been reason behind high ratios of macromolecules and nanoparticles in tumours compared to
normal tissues.
Perforin: drug target in cancer and transplantation medicine
The pore-forming immune effector perforin is an essential weapon of the immune system. It
is produced and secreted by cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells in
order to destroy virally-infected or oncogenic targets.
However, unwanted perforin function is central to the failure of certain transplantation
therapies and pathogenesis of serious diseases. For example, residual host NK activity in
patients mediates graft destruction and the high mortality rate (~ 30%) of patients receiving
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allogeneic bone marrow transplantation therapy for leukaemia. There is also strong evidence
that perforin-dependent CTL function is responsible for pancreatic islet destruction in
diabetes and graft rejection in organ transplantation. Currently, there is no drug that
specifically and effectively inhibits perforin-dependent NK or CTL function.Target sites on
perforin, derived from crystal structure data, make attractive extracellular targets for
monoclonal antibody (mAb) drug development.
Conclusion
An ongoing challenge in the field of development of novel target sites as well as novel drugs
which is highly efficient as well as less toxic to the host has been somehow limited by the
invent of novel screening and drug development methods. The ultimate goal of drug delivery
research is to help patients by developing clinically useful formulations. During the last
several decades controlled drug delivery technology has advanced significantly, leading to
the development of various clinical formulations improving patient compliance and
convenience. It would we worthwhile in continuing research in this topic to find novel target
sites and novel drugs for human use.
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