Accession Number : ADA540515


Title :   Small-Molecule Inhibitor Leads of Ribosome-Inactivating Proteins Developed Using the Doorstop Approach


Descriptive Note : Journal article


Corporate Author : WALTER REED ARMY INST OF RESEARCH SILVER SPRING MD


Personal Author(s) : Pang, Yuan-Ping ; Park, Jewn G ; Wang, Shaohua ; Vummenthala, Anuradha ; Mishra, Rajesh K ; McLaughlin, John E ; Di, ROng ; Kahn, Jennifer N ; Tumer, Nilgun E ; Janosi, Laszlo


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a540515.pdf


Report Date : Mar 2011


Pagination or Media Count : 17


Abstract : Ribosome-inactivating proteins (RIPs) are toxic because they bind to 28S rRNA and depurinate a specific adenine residue from the a-sarcin/ricin loop (SRL), thereby inhibiting protein synthesis. Shiga-like toxins (Stx1 and Stx2), produced by Escherichia coli, are RIPs that cause outbreaks of foodborne diseases with significant morbidity and mortality. Ricin produced by the castor bean plant, is another RIP lethal to mammals. Currently, no US Food and Drug Administration approved vaccines nor therapeutics exist to protect against ricin, Shiga-like toxins, or other RIPs. Development of effective small-molecule RIP inhibitors as therapeutics is challenging because strong electrostatic interactions at the RIPNSRL interface make drug-like molecules ineffective in competing with the rRNA for binding to RIPs. Herein, we report small molecules that show up to 20% cell protection against ricin or Stx2 at a drug concentration of 300 nM. These molecules were discovered using the doorstop approach, a new approach to protein polynucleotide inhibitors that identifies small molecules as doorstops to prevent an active-site residue of an RIP (e.g., Tyr80 of ricin or Tyr77 of Stx2) from adopting an active conformation thereby blocking the function of the protein rather than contenders in the competition for binding to the RIP. This work offers promising leads for developing RIP therapeutics. The results suggest that the doorstop approach might also be applicable in the development of other protein-polynucleotide inhibitors as antiviral agents such as inhibitors of the ZDNA binding proteins in poxviruses. This work also calls for careful chemical and biological characterization of drug leads obtained from chemical screens to avoid the identification of irrelevant chemical structures and to avoid the interference caused by direct interactions between the chemicals being screened and the luciferase reporter used in screening assays.


Descriptors :   *PROTEINS , *MOLECULAR STRUCTURE , *RIBONUCLEIC ACIDS , ESCHERICHIA COLI , THERAPY , LETHALITY , DRUGS , POX VIRUSES , FOOD , RICIN , ELECTROSTATICS , BIOSYNTHESIS , INACTIVATION , ADENINE , LUCIFERASE , DISEASES , REPORTS , MAMMALS , ANTIVIRAL AGENTS


Subject Categories : Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE