Where are all the ribosome drugs?

Jonathan Ouyang Ribosomes rule life. They probably enabled life to exist in the first place, by being responsible for 100% of protein synthesis; we define species using them (archaea were discovered by 16S rRNA phylogeny) [1]; they’re autocatalytic universal constructors responsible for the limit on replication speed [2], [3], [4], [5], [6], and their biogenesis is a major determinant of most cellular processes (e.g. transcription, translation, splicing, and metabolism). [7], [8], [9], [10][note 1] If the human body is a scaffold that supports the brain, the cell is a scaffold that supports ribosomes. The majority of antibiotic classes target the ribosome in some fashion. [11], [12], [13][note 2] Ribosomes and their regulation are implicated not just in so-called ribosomopathies but also in fundamental malfunctions in cancer, neurodegenerative, and geropathological diseases. [14], [15], [16], [17], [18], [19] The ribosome is simultaneously the most successfully drugged target in the history of medicine and one of the least. So, then, where are all the ribosome drugs? From sledgehammers to leversThe use of the first ribosome-targeting drugs can be traced to before 550 CE, where ancient Sudanese societies consumed beverages fermented with Streptomyces, a bacteria that produces tetracycline [20], [21][note 3], which binds the 30S subunit of the (bacterial) ribosome to inhibit translation, and now names an entire class of antibiotics. [11], [12] Other ribosome-targeting antibiotics include chloramphenicol, the aminoglycosides, spectinomycins, macrolides, oxazolidinones, lincosamides, streptogramins, pleuromutilins… all of which are generally broad-spectrum protein synthesis inhibitors and which therefore shut down cellular activity. [22][note 4] Although the mechanisms of actions of these drugs are varied, all of them act via disruption of some key step during canonical translation. These “sledgehammers” work spectacularly for two reasons: one, they are relatively unsel