title: Co-lethality studied as an asset against viral drug escape: the HIV protease case.
abstract: BACKGROUND
  Co-lethality, or synthetic lethality is the documented genetic situation where two, separately non-lethal mutations, become lethal when combined in one genome. Each mutation is called a "synthetic lethal" (SL) or a co-lethal. Like invariant positions, SL sets (SL linked couples) are choice targets for drug design against fast-escaping RNA viruses: mutational viral escape by loss of affinity to the drug may induce (synthetic) lethality.
  
  
  RESULTS
  From an amino acid sequence alignment of the HIV protease, we detected the potential SL couples, potential SL sets, and invariant positions. From the 3D structure of the same protein we focused on the ones that were close to each other and accessible on the protein surface, to possibly bind putative drugs. We aligned 24,155 HIV protease amino acid sequences and identified 290 potential SL couples and 25 invariant positions. After applying the distance and accessibility filter, three candidate drug design targets of respectively 7 (under the flap), 4 (in the cantilever) and 5 (in the fulcrum) amino acid positions were found.
  
  
  CONCLUSIONS
  These three replication-critical targets, located outside of the active site, are key to our anti-escape strategy. Indeed, biological evidence shows that 2/3 of those target positions perform essential biological functions. Their mutational variations to escape antiviral medication could be lethal, thus limiting the apparition of drug-resistant strains.
  
  
  METHODS
  This article was reviewed by Arcady Mushegian, Shamil Sunyaev and Claus Wilke.
authors.affiliation: Atelier de Bio Informatique, F-75005, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouillet
authors.forename: Thomas
authors.initials: T
authors.lastname: Valere
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ollivier
authors.forename: Laurent
authors.initials: L
authors.lastname: Marsan
authors.forename: Anne
authors.initials: A
authors.lastname: Vanet
mesh_terms: D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics*; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D009154:Mutation / Q000235:genetics / Q000502:physiology
chemical_list: D016333:HIV Protease