mRNA translation regulation
A vast novel target space
Regulation of protein expression by targeting mRNA is a validated approach in drug development, as indicated by RNAi-based therapeutics. However, these drugs are not small molecules, which severely limits their use as a therapeutics strategy. Targeting mRNA secondary structures with small molecules is an emerging field. However, the therapeutic outcome of binding to mRNA with small molecules is not validated and this approach can’t achieve tissue selectivity since such drugs would bind to the target mRNA everywhere it is expressed.
Anima’s approach broadens the mRNA regulation target space by identifying novel regulatory proteins that have specific biological roles in coordinating and regulating mRNA translation in a tissue-specific manner. Anima’s Translation Control platform not only identifies drug candidates, but intrinsically helps in elucidating the pathways and mechanisms-of-action of these molecules.
Our small molecules are targeting novel targets in the translation of mRNA regulation: for example, RNA binding proteins (RBPs), mRNA modifying proteins (epitranscriptomics), modifiers of ribosomal proteins, ribosome accessory proteins, regulation of tRNA abundance, tRNA modification.
Multiple targets in translation regulation beyond mRNA processing
mRNA is modified at the nucleotide levels (epitranscriptomics) and is bound by proteins to protect it from degradation and to enable its processing and transport. Changes in mRNA modifications influence its processing and regulate the association of RNA binding proteins (RBPs), the recognition of the mRNA by ribosome accessory factors and determine the rate of translation by ribosomes.
Not all ribosomes are the same and there are many accessory proteins that are mRNA selective or tissue specific. These regulate the recruitment of mRNA to the ribosome and/or the rate at which the ribosome can advance the mRNA. The activity of these accessory proteins is regulated by different modifications, such as phosphorylation and methylation.
RNA binding proteins (RBPs) bind to mRNA and are involved in mRNA transport, half-life, intracellular localization and recruitment to ribosomes. RBPs undergo modifications that regulate their stability, ability to bind mRNA, and their recruitment to ribosomes. The proteins which modify RBPs are also targets in translation regulation.
tRNA is the most highly modified nucleic acid, with an average of 13 modifications per one tRNA (76 NT long). These modifications regulate the ability of tRNA to be loaded with amino acids, as well as its affinity to the codon it is encoding. These regulate the rate of translation.
mRNA translation regulation down or up on demand
Proteins that interact with mRNA, RNA binding proteins (RBPs): As an example, RBPs bind to an mRNA molecule as a physical obstacle in the way of ribosomes. Ribosomes cannot translate the mRNA molecule, but when the appropriate signal arrives, the RBP is released from the mRNA by an enzyme (T2). Thus, if T2 is inhibited with a small molecule, translation will be inhibited.
Proteins that specifically regulate ribosome activity: Regulatory proteins, or ribosome associate proteins, are expressed in a tissue and cell specific manner. These are used to activate or inhibit translation of target proteins by ribosomes and constitute novel targets, which can both up and down regulate translation, in a selective and tissue specific manner.
Enhancers of protein translation
Targeting the regulatory mechanisms of mRNA translation enables the discovery of compounds that not only decrease but can also increase protein translation in a tissue-selective manner.
Compounds which increase the rate of translation of Collagen I, increase the light (upper panel, compound 1 and 2). These compounds enhance production of Collagen I protein (lower panel).