title: A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants.
abstract: BACKGROUND
  The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1.
  
  
  RESULTS
  We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective.
  
  
  CONCLUSIONS
  Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD 21702-1201, USA.
authors.forename: Barry C
authors.initials: BC
authors.lastname: Johnson
authors.forename: Gary T
authors.initials: GT
authors.lastname: Pauly
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Disha
authors.initials: D
authors.lastname: Patel
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bauman
authors.forename: Heather L
authors.initials: HL
authors.lastname: Baker
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
authors.forename: Joel P
authors.initials: JP
authors.lastname: Schneider
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
mesh_terms: D002460:Cell Line; D003461:Crystallography; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000068696:Rilpivirine
chemical_list: D009570:Nitriles; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine