Biochemistry Online: An Approach Based on Chemical Logic

CHAPTER 5 - BINDING

E: MODERN METHODS IN DRUG DEVELOPMENT

BIOCHEMISTRY - DR. JAKUBOWSKI

Last Updated: 03/31/16

Learning Goals/Objectives for Chapter 5E: After class and this reading, students will be able to

describe the basis for the following methods used to design drugs:
1. combinatorial drug development
2. computer-aided design
3. in situ click chemistry
describe drugs that target specific
1. proteins
2. DNA
3. RNA
describe the benefit of drugs that
1. are mutivalent
2. perturb equilibrium

E7. RNA Binding Drugs

One of the best new alternatives is to design a RNA molecule complementary to a given mRNA for a specific protein selected for inhibition. This antisense RNA forms a dsRNA when it binds to the mRNA and inhibits translation of the mRNA.

Figure: antisense RNA forms a dsRNA

Cells can be altered through genetic engineering to make an antisense RNA within the cells by inserting an inverted copy of the target cDNA for the gene of interest into the cell, and allowing the cell to manufacture its own drug!

Figure: Cells can be altered through genetic engineering to make an antisense RNA within the cells

Even more exciting is the use of RNAis (RNA inference) for disease therapy. In contrast to traditional drugs, RNAis are one of nature's proven methods to inhibit gene transcription or RNA translation (mainly from viruses). Even though it was only discovered five years ago, it may be only a few years before drug trials based on RNAi take place. Especially promising are trials for siRNAs that inhibit HIV. To show that it works in organisms, mice were infected with a fusion of hepatitis C gene segment and a gene for a fluorescent protein luciferase. Specific siRNAs-treated mice showed a dramatic decrease of fluorescence, but not those treated with a nonspecific RNAi. As with other drugs, getting them into target cells is proving difficult. Simple liposome-encapsulated siRNAs apparently are not as effective as hoped. Carrying the siRNA into the cells with virus is yet another idea. Some companies pursuing this technology are shown below.

Benitec
Alnylam Pharmaceuticals
Antisense drugs: AVI BioPharma
Calando: RONDEL (RNAi/Oligonucleotide Nanoparticle Delivery) in which siRNA is bound to a block polymer of a positive polymer interspersed among cyclodexdrins, protecting the. siRNA from degrations by nucleases. These self-associate to form nanopartaicles. Adamantine (hydophobic) linked to polyethylene glycol (polar) to which targeting proteins (like transferrin) are attached are added to the nanoparticles, leading to PEG-dependent stabilization of the nanoparticle (and si-RNA) and transferrin-dependent delivery to target cancer cells, which over express transferrin receptors.

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