Varuni Ankolekar, Clinical Data Manager
Traditionally, the discovery of drugs was done by recognizing the active ingredients from traditional remedies or unexpectedly. Later, Scientists discovered that the interaction of specific chemicals in the drug with biological molecules of the human body serves the purpose of the drug. Later, Chemical pharmacological approaches were made to identify the molecule that has desired medicinal effect. More recently, the sequence of the human genome has led to a reverse pharmacological approach of drug discovery to new diseases.
Chemical pharmacology v/s Reverse pharmacology:
Chemical pharmacology is a Chemical library of artificial molecules, natural elements or extracts that were assessed in cells or organisms to detect substances that had a suitable therapeutic effect in a process.
Also known as target-based drug discovery (TDD) is identifying specific protein target for beneficial therapeutic effects. This became widespread after human genome sequencing.
Re-engineered genes:
Nucleotides of DNA code are copied into RNA whenever proteins are produced. RNA is read in the form of Codons which corresponds to specific amino acids. There are 64 possible three-letter nucleotide sequences (61 representing amino acids, and 3 are stop Codons). Genetic code could be redundant since a single amino acid may be coded for by more than one codon.
Scientists have re-engineered genes and other bits of protein-building components, to build proteins with distinctive chemical properties beneficial in drug preparations. However, it is a cumbersome method. Primarily, researchers utilized cellular components to incorporate unnatural amino acids whenever a particular stop codon appeared. However, it could add only one at a time. Modern methodology of rewriting bacterium’s genome has led to overcoming the laborious method and helps in adding several amino acids to a protein at a time. This could antibiotics and antitumor drugs
In 2019, Chin and his colleagues used CRISPR-Cas9 gene-editing tool to create an Escherichia coli strain known as Syn61. They recoded 18,000 serine codons of bacteria by replacing UCG, UCA and the stop codon UAG with their “synonyms,” AGC, AGU, and UAA, respectively to produce an organism with a 61-codon genome, which utilizes 59 codons to translate the 20 amino acids and facilitates the removal of a previously essential transfer RNA. The replacement of these codons made the incorporation of serine into the appropriate locations of Syn61’s growing proteins. But the UCG, UCA, and UAG codons were now considered as “blanks” that did not code for anything in the protein and were ready to be used per requirement.
The genes of transfer RNAs (tRNAs) in Syn61 that identify UGC and UCA and insert serine into a growing protein were removed along with the chemical compound that ends protein synthesis when the UAG stop codon appears. The researchers then inserted back genes with novel tRNAs that would incorporate unnatural amino acids when UGC, UCA, or UAG codons were encountered. Ultimately, wherever the unnatural amino acids were required they wrote those codons back into the genome. This permitted them to add three unnatural amino acids at once into individual proteins.
Hence, this could be a reliable, advanced, and robust method that to be implemented for drug discovery and could be a boon to all clinical researchers and biotech companies.
Also read:World Food Safety Day 2021
References:
- Drug discovery- https://en.wikipedia.org/wiki/Drug_discovery
- New approach of rewriting bacterial genome: https://www.sciencemag.org/news/2021/06/new-approach-rewriting-bacteria-s-genetic-code-could-lead-novel-medicines
- More about bacterial genome: https://www.nature.com/articles/s41586-019-1192-5
- Fredens, J., Wang, K., de la Torre, D. et al. Total synthesis of Escherichia coli with a recoded genome. Nature569, 514–518 (2019). https://doi.org/10.1038/s41586-019-1192-5
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