title: In vitro and structural evaluation of PL-100 as a potential second-generation HIV-1 protease inhibitor.
abstract: OBJECTIVE
  HIV-1 protease inhibitors (PIs) are key components of HIV therapy. PL-100 is a novel lysine sulphonamide that demonstrates potent antiviral activity against multiresistant HIV-1 strains as well as a higher genetic barrier for development of resistance mutations compared with first-generation PIs. In the present study, we compared the antiviral activity of PL-100 against HIV-1 subtype B with that of darunavir.
  
  
  METHODS
  We used tissue culture experiments to evaluate the in vitro development of resistance to PL-100 and tested the antiviral activity of several clinically approved PIs against PL-100-selected resistant variants. Structural modelling was also used to compare the binding of PL-100 and darunavir to the HIV-1 protease (PR) enzyme.
  
  
  RESULTS
  PL-100-resistant variants that emerged within 8-48 weeks showed low- to high-level resistance (3.5- to 21.6-fold) to PL-100, but commonly retained susceptibility to darunavir, which, in contrast, did not select for resistance mutations over a period of 40 weeks. Structural modelling demonstrated that binding of PL-100 was predominantly based on polar interactions and delocalized hydrophobic interactions through its diphenyl groups, while darunavir has numerous interactions with PR that include hydrogen bonding to PR backbone oxygens at amino acid positions A28, D29 and D30 via di-tetrahydrofuran (di-THF) groups.
  
  
  CONCLUSIONS
  Hydrogen-bonding contacts and the di-THF group in darunavir, as well as the hydrophobic nature of PL-100, contribute to PI binding and a high genetic barrier for resistance. Redesigning the structure of PL-100 to include a di-THF group might improve it.
authors.affiliation: McGill University AIDS Centre,  Lady Davis Institute, Jewish General Hospital, Montreal, Quebec,  Canada.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Asahchop
authors.forename: Maureen
authors.initials: M
authors.lastname: Oliveira
authors.forename: Peter K
authors.initials: PK
authors.lastname: Quashie
authors.forename: Daniela
authors.initials: D
authors.lastname: Moisi
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Martinez-Cajas
authors.forename: Bluma G
authors.initials: BG
authors.lastname: Brenner
authors.forename: Cecile L
authors.initials: CL
authors.lastname: Tremblay
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002219:Carbamates; D017320:HIV Protease Inhibitors; C525732:PL 100; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1