Protein synthesis inhibitor

File:Ribosome mRNA translation en.svg

A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.{{cite web |url=http://www.columbia.edu/itc/hs/medical/pathophys/id/2009/proteinNotes.pdf|title=Protein Synthesis Inhibitors|author=Frank Lowy|website=Columbia University|access-date=2021-01-27}}

Image:Protein translation.gif is a biological machine that utilizes protein dynamics on nanoscales to translate RNA into proteins]]

While a broad interpretation of this definition could be used to describe nearly any compound depending on concentration, in practice, it usually refers to compounds that act at the molecular level on translational machinery (either the ribosome itself or the translation factor),{{cite web |url=http://ocw.mit.edu/OcwWeb/Biology/7-344Spring-2007/LectureNotes/index.htm |work=MIT OpenCourseWare |title= 7.344 Antibiotics, Toxins, and Protein Engineering, Spring 2007 }} taking advantages of the major differences between prokaryotic and eukaryotic ribosome structures.{{citation needed|date=March 2019}}

Mechanism

In general, protein synthesis inhibitors work at different stages of bacterial mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer, and bacterial translocation) and termination:

=Earlier stages=

Rifamycin inhibits bacterial DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit.{{cn|date=March 2023}}
alpha-Amanitin is a powerful inhibitor of eukaryotic DNA transcription machinery.{{cn|date=March 2023}}

=Initiation=

Linezolid acts at the initiation stage,{{cite journal |vauthors=Swaney SM, Aoki H, Ganoza MC, Shinabarger DL |title=The Oxazolidinone Linezolid Inhibits Initiation of Protein Synthesis in Bacteria |journal=Antimicrob. Agents Chemother. |volume=42 |issue=12 |pages=3251–3255 |date=December 1998 |pmid=9835522 |pmc=106030 |doi= 10.1128/AAC.42.12.3251}} probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.{{cite journal |vauthors=Skripkin E, McConnell TS, DeVito J, etal |title=Rχ-01, a New Family of Oxazolidinones That Overcome Ribosome-Based Linezolid Resistance |journal=Antimicrobial Agents and Chemotherapy |volume=52 |issue=10 |pages=3550–3557 |date=October 2008 |pmid=18663023 |pmc=2565890 |doi=10.1128/AAC.01193-07}}

= Ribosome assembly =

Aminoglycosides prevent ribosome assembly by binding to the bacterial 30S ribosomal subunit.{{cite journal|last1=Mehta|first1=Roopal|last2=Champney|first2=W. Scott|year=2003|title=Neomycin and Paromomycin Inhibit 30S Ribosomal Subunit Assembly in Staphylococcus aureus|journal=Current Microbiology|volume=47|issue=3|pages=237–43|doi=10.1007/s00284-002-3945-9|pmid=14570276|s2cid=23170091 }}

=Aminoacyl tRNA entry=

Tetracyclines and Tigecycline{{cite journal

|vauthors=Slover CM, Rodvold KA, Danziger LH | title = Tigecycline: a novel broad-spectrum antimicrobial

| journal = Ann Pharmacother

| volume = 41

| issue = 6

| pages = 965–972

|date=June 2007

| doi = 10.1345/aph.1H543

| url = http://www.medscape.com/viewarticle/557981_2

| access-date = 2009-12-19

| pmid = 17519296

| s2cid = 5686856

| url-access = subscription

}} (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs.

=Proofreading=

Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination.{{cite web | url=http://pharmamotion.com.ar/protein-synthesis-inhibitors-aminoglycosides-mechanism-of-action-animation-classification-of-agents/ | work=Pharmamotion | title=Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents | author=Flavio Guzmán | date=2008-08-12 | url-status=dead | archive-url=https://web.archive.org/web/20100312134115/http://pharmamotion.com.ar/protein-synthesis-inhibitors-aminoglycosides-mechanism-of-action-animation-classification-of-agents/ | archive-date=2010-03-12 }}

=Peptidyl transfer=

Chloramphenicol blocks the peptidyl transfer step of elongation on the 50S ribosomal subunit in both bacteria and mitochondria.
Macrolides (as well as inhibiting ribosomal translocation[https://web.archive.org/web/20081226204524/http://pharmamotion.com.ar/protein-synthesis-inhibitors-macrolides-mechanism-of-action-animation-classification-of-agents/ Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents] Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009 and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer.
Streptogramins such as Quinupristin/dalfopristin act synergistically, with dalfopristin, enhancing the binding of quinupristin, as well as inhibiting peptidyl transfer.[https://books.google.com/books?id=ekyv3I9ccIQC Page 212] in:

Title: Hugo and Russell's pharmaceutical microbiology

Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman

Edition: 7, illustrated

Publisher: Wiley-Blackwell, 2004

Length: 481 pages Quinupristin binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide, as well as causing incomplete chains to be released.

Geneticin, also called G418, inhibits the elongation step in both prokaryotic and eukaryotic ribosomes.{{cite web|url=https://www.thermofisher.com/us/en/home/life-science/cell-culture/transfection/selection/g418.html|title=Geneticin|work=Thermo Fisher Scientific}}
Trichothecene mycotoxins are potent and non selective inhibitors of peptide elongation.{{cite journal|last1=Shifrin|first1=Victor I.|last2=Anderson|first2=Paul|title=Trichothecene Mycotoxins Trigger a Ribotoxic Stress Response That Activates c-Jun N-terminal Kinase and p38 Mitogen-activated Protein Kinase and Induces Apoptosis|journal=Journal of Biological Chemistry|volume=274|issue=20|year=1999|pages=13985–13992|issn=0021-9258|doi=10.1074/jbc.274.20.13985|pmid=10318810 |doi-access=free}}

=Ribosomal translocation=

Macrolides, clindamycin[http://sitemaker.umich.edu/mc3/clindamycin Wisteria Lane cases → CLINDAMYCIN] {{Webarchive|url=https://archive.today/20120718035925/http://sitemaker.umich.edu/mc3/clindamycin |date=2012-07-18 }} University of Michigan. Retrieved on July 31, 2009 and aminoglycosides (with all these three having other potential mechanisms of action as well), have evidence of inhibition of ribosomal translocation.
Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome.
Ricin inhibits elongation by enzymatically modifying an rRNA of the eukaryotic 60S ribosomal subunit.{{cite journal|date=October 1988|title=Ricin binding and protein synthesis inhibition in human hematopoietic cell lines|url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=3167211|journal=Blood|volume=72|issue=4|pages=1357–1363|doi=10.1182/blood.V72.4.1357.1357|pmid=3167211|vauthors=Leonard JE, Grothaus CD, Taetle R|doi-access=free|url-access=subscription}}{{cite journal|date=June 1988|title=Ricin and alpha-sarcin alter the conformation of 60S ribosomal subunits at neighboring but different sites|journal=Eur. J. Biochem.|volume=174|issue=3|pages=459–463|doi=10.1111/j.1432-1033.1988.tb14120.x|pmid=3391162|vauthors=Terao K, Uchiumi T, Endo Y, Ogata K|doi-access=free}}

=Termination=

Macrolides{{cite journal

| author = Menninger JR

| title = Mechanism of inhibition of protein synthesis by macrolide and lincosamide antibiotics

| journal = J Basic Clin Physiol Pharmacol

| volume = 6

| issue = 3–4

| pages = 229–250

| year = 1995

| pmid = 8852269

| doi = 10.1515/JBCPP.1995.6.3-4.229

| s2cid = 36166592

}}{{cite journal

|vauthors=Tenson T, Lovmar M, Ehrenberg M | title = The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome

| journal = J. Mol. Biol.

| volume = 330

| issue = 5

| pages = 1005–1014

|date=July 2003

| doi = 10.1016/S0022-2836(03)00662-4

| pmid = 12860123

}} and clindamycin (both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome.

Puromycin has a structure similar to that of the tyrosinyl aminoacyl-tRNA. Thus, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome, causing a premature termination of polypeptide synthesis.
Streptogramins also cause premature release of the peptide chain.