Journal Article

Emergence of prions selectively resistant to combination drug therapy

Beauchemin, Kathryn S., Burke, Cassandra M., Mark, Kenneth M. K., Kun, Judit, Supattapone, Surachai

2020

Overview

Prions are unorthodox infectious agents that replicate by templating misfolded conformations of a host-encoded glycoprotein, collectively termed PrPSc. Prion diseases are invariably fatal and currently incurable, but oral drugs that can prolong incubation times in prion-infected mice have been developed. Here, we tested the efficacy of combination therapy with two such drugs, IND24 and Anle138b, in scrapie-infected mice. The results indicate that combination therapy was no more effective than either IND24 or Anle138b monotherapy in prolonging scrapie incubation times. Moreover, combination therapy induced the formation of a new prion strain that is specifically resistant to the combination regimen but susceptible to Anle138b. To our knowledge, this is the first report of a pathogen with specific resistance to combination therapy despite being susceptible to monotherapy. Our findings also suggest that combination therapy may be a less effective strategy for treating prions than conventional pathogens.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Age / Animals / Benzodioxoles - pharmacology / Biochemistry / Biology / Biology and Life Sciences / Brain / Burke, Kenneth / Chemotherapy / Combination drug therapy / Creutzfeldt-Jakob disease / Drug resistance / Drug therapy / Drug Therapy, Combination / Drugs / Glycoproteins / Health aspects / Infections / Medicine / Medicine and Health Sciences / Mice / Mutation / Oral administration / Pathogens / Patient outcomes / Prion protein / Prions / Prions (Proteins) / PrPSc Proteins - metabolism / PrPSc Proteins - pathogenicity / Pyrazoles - pharmacology / Research and Analysis Methods / Scrapie / Scrapie - drug therapy / Scrapie - metabolism / Scrapie - pathology