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SYNTHESIS OF A HETERODIMERIC PEPTIDE TARGETING CANCER CELLS

SYNTHESIS OF A HETERODIMERIC PEPTIDE TARGETING CANCER CELLS

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An essay for the 2012 Undergraduate Awards Competition by William Whyte. Originally submitted for pharmacy , with lecturer Marc Devocelle in the category of Medical Sciences
An essay for the 2012 Undergraduate Awards Competition by William Whyte. Originally submitted for pharmacy , with lecturer Marc Devocelle in the category of Medical Sciences

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Published by: Undergraduate Awards on Aug 30, 2012
Copyright:Attribution Non-commercial

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05/01/2014

 
SYNTHESIS OF A HETERODIMERIC PEPTIDE TARGETING CANCER CELLSAbstract
In the search for the magic bullet for cancer treatment many different agents have beenused with varying success. This search by empirical design for a successful treatmentmeans the mechanism of how certain agents kill the cell is poorly understood. This haslead to list of conventional treatments with toxic side effects and susceptibility to developresistance. The aim is to develop a targeted anti-cancer therapy for dividing and nondividing cancer cells and which induces cell death by a specific mechanism (apoptosis)and thereby does not affect healthy cells. In this project we focused on two biomoleculesto help achieve the aim of selectivity, less toxicity and decreased susceptibility toresistance.The BH3 domain of Bid is the first of these molecules. It is a member of the apoptoticregulatory family and it has the ability to bind to anti-apoptotic proteins and inactivatethem. This enhances the apoptotic response of cancer cells to internal and external stimulisuch as chemotherapy. Cancer cells do not undergo cell death so targeting cell deathreceptors offers a novel therapeutic strategy .This protein has the capability to be aneffective cancer treatment however it has many problems to overcome including poor  bioavailability, lack of selectivity for cancer cells and poor cellular uptake.Buforin IIb is the second of these molecules. It is a host defence peptide which hasnatural selectivity for cancer cells and anticancer activity through mitochondriadependent apoptosis; importantly it also can act as a vector to bring other peptides acrossthe plasma membrane into the cytosol.Our main objective was to conjugate both BH3 (Bid) and Buforin IIb using a disulphide bond. BH3(Bid) has already been attached to a vector (octaarginine) in the past. Theunique component in this experiment is the extra therapeutic potential Buforin has alongwith its capacity to act as a vector. Buforin has natural selectivity for cancer cells, it isactive on dividing and non dividing cells and does not easily select resistant mutants .
 
The contribution of the Buforin activity could overcome resistance occurring through the pathway in which the BH3 bid peptide is acting as they both cause the release of cytochrome c downstream. BH3(Bid) has anticancer activity in the nanomolar scale whileBuforin has activity tin the micromolar scale. It is hoped that the BuforinIIb can at leasthave an additive anticancer effect if not a synergistic anticancer effect with the BH3(Bid)To conclude, it is hoped that the heterodimer will selectively target cancer cells,translocate across the plasma membrane efficiently and once inside the cell be cleaveddue to inherent reducing condition. The overall aim of the project was to synthesise thedesired peptide in a sufficient yield that could be scaled up and also tested for its efficacyin vitro. This project addressed the synthetic difficulties associated with the method andthe protocol developed has since been used to produce successfully sufficient quantitiesof target product to allow biological testing.
 
Introduction
Cancer is a group of exceptionally complicated diseases characterised by uncontrollableand unregulated cell proliferation. It occurs through genetic mutations and is typified bycells that do not die. The objective of cancer therapy is to induce cell death in thesecancerous cells without inducing non-target toxicity This search by empirical design for asuccessful treatment means the mechanism of how certain agents kill the cell is poorlyunderstood. This has lead to list of conventional treatments with serious limitations.Limitations include susceptibility to develop a drug resistance , poor therapeutic responseto treatment in slowly dividing cancer cells and debilitating side effects ranging fromnausea, vomiting and hair loss to myelosuppresion and thrombocytopeniaFor a normal cell to become a cancerous cell it must break a number of rules or checkpoints that normal cells obey. These rules such as ignoring cell cycle checkpointsand generation of their own growth signal would normally cause the activation of theintrinsic apoptotic pathway. However cancerous cells can override this by a number of different of mechanism such as increasing the ratio of anti-apoptotic proteins to pro-apoptotic proteins.These proteins are members of the Bcl-2 family which partly regulates the apoptosis pathway. Apoptosis is the main form of programmed cell death in humans and itsderegulation is implicated in many diseases such as cancer, autoimmunity and diabetes .Changes in the pathway can impart resistance to internal apoptotic triggers such asoncogenes, hypoxia, growth factor withdrawal and importantly external triggers such aschemotherapeutics. Apoptosis is regulated by an intrinsic and extrinsic pathway. Theextrinsic pathway can be activated by the tumour necrosis factor receptor while theintrinsic pathway or mitochondrial pathway can be activated or deactivated by the Bcl-2family.The family contains twenty members and is divided into three subgroups depending ontheir function, anti-apoptotic proteins (e.g., BCL-2, BCL-XL, and MCL-1), pro-apoptoticeffector proteins (BAX and BAK) and BH3 only proteins (BIM, BID, BAD, BMF, Noxa,

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