This document provides information on antisense molecules and aptamers. It discusses how antisense oligonucleotides work by hybridizing with mRNA in a sequence-specific manner, leading to mRNA degradation or translational arrest. Several antisense drugs have been approved to treat diseases like cytomegalovirus retinitis and spinal muscular atrophy. The document also introduces aptamers, which are nucleic acid or peptide molecules that can bind to proteins. Aptamers are identified through a process called SELEX and have potential for therapeutic use.
ANTISENSE MOLECULES AND APTAMERS AS DRUGS OF FUTURE.pptx
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Antisense molecules and aptamers
PRESENTED BY:
MISS SYEDA HASSAN YAMEEN
ROLL NO.170720886008
Subject:MOLECULAR PHARMACEUTICS
NANO TECH AND TARGETED DDS
UNDER THE GUIDANCE OF:
DR. ABDUL MANNAN
M.PHARM,Ph.D
DEPARTMENT:PHARMACEUTICS.
DECCAN SCHOOL OF PHARMACY
Dar-us salam, Aghapura, Hyderabad.-504001
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Oligonucleotides
• Oligonucleotides are unmodified or chemically modified single-stranded DNA molecules.
In general, they are relatively short (13–25 nucleotides)
• An antisense oligonucleotide (ASO) is a short strand of deoxyribonucleotide analogue
that hybridizes with the complementary mRNA in a sequence-specific manner via
Watson-Crick base pairing. Formation of the ASO-mRNA heteroduplex either triggers
RNase H activity, leading to mRNA degradation,
induces translational arrest by steric hindrance of ribosomal activity,
interferes with mRNA maturation by inhibiting splicing or
destabilizes pre-mRNA in the nucleus, resulting in downregulation of target protein
expression.
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MECHANISM:
Antisense mechanisms of action.
ASOs interfere with pre/mRNA in two ways:
(i) by promoting their cleavage via RNaseH1 and
(ii) by blocking processing events such as 5′capping of the pre-RNA, exon splicing,(process by which
introns non coding region of genes are excised out and exons coding regions are joined together)
and the interaction of mRNA with ribosomal subunits (40S and 60S) of the translation initiation
complex.
(iii) Stearic block
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• Absorption :1/2 life 1 hr peak plasma conc.3-4 hr
• Absorbed by endocytosis forms endosome degraded by lysosome
• Distribution non linear kinetic
• Slow plasma clearance at high dose
• Cmax 1-3 hr after subcutaneous and low on i.v injection
• More than 90%is protein bound
• Metabolism endonucleases mediated cleavage of deoxy nucleotide
at center
• Elimination high protein bound prevents glomerular filteration
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ANTISENSE DRUGS APPROVED FOR DISEASE
Formivirsen first ASO drug approved by the FDA for
cytomegalovirus (CMV) retinitis in
immunocompromised AIDS patients
Mipomersen is a second-generation ASO familial hypercholesterolemia, a rare genetic disorder
characterized by high levels of low density lipoprotein
(LDL) cholesterol
Nusinersen spinal muscular atrophy (SMA), SMA is caused by the
loss of survival of motor neuron 1 (SMN1) expression
Eteplirsen,Casimersen (recentlyapproved) third-
generation
Duchenne muscular dystrophy (DMD) progressive
muscular weakness.
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INTRODUCTION:
• Aptamers {aptus fit , meros part}are small single-stranded or double-stranded
nucle-ic acid segments that can directly interact with proteins. Aptamer-
assisted interaction can be used to interfere with the molecular functions of
disease-implicated proteins or those that participate in the transcription or
translation processes,thus inhibiting the processing of target therapeutic
proteins.
• More specifically, aptamers can be classified as
• DNA or RNA or XNA aptamers. They consist of (usually short) strands of
oligonucleotides.
• Peptide aptamers. They consist of one (or more) short variable peptide
domains, attached at both ends to a protein scaffold.
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• NUCLEIC ACID DNA/ RNA are generated via in-vitro selection or through
SELEX (systematic evolution of ligands by exponential enrichment) to targets ranging
from small entities such as heavy metal ions to large entities like cells. On the molecular
level, an aptamer binds to its target through various non-covalent interactions such as,
electrostatic interactions, hydrophobic interactions, and induced fitting. Aptamers are
useful in biotechnological and therapeutic applications as they offer molecular recognition
properties that rival those of the commonly used biomolecule, antibodies.
• Peptide aptamers are artificial proteins selected or engineered to bind specific target
molecules
• X-Aptamers are a new generation of aptamers designed to improve on the binding and
versatility of regular DNA/RNA- based aptamers.
• Affimer molecules are small proteins that bind to target proteins with affinity in the
nanomolar range.
