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An integrated European effort to develop vaginal/rectal HIV preventive drugs

An integrated European effort to develop vaginal/rectal HIV preventive drugs. Guido Vanham and Kevin Ariën , Virology Unit, Institute of Tropical Medicine, Antwerp. CHAARM: objectives. To develop new HIV antivirals for vaginal/rectal HIV prevention

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An integrated European effort to develop vaginal/rectal HIV preventive drugs

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  1. An integrated European effort to develop vaginal/rectal HIV preventive drugs Guido Vanham and Kevin Ariën, Virology Unit, Institute of Tropical Medicine, Antwerp

  2. CHAARM: objectives • To develop new HIV antivirals for vaginal/rectal HIV prevention • To develop microbicide combinations and coformulations • To test efficacy of microbicide (combinations) in macaque models of vaginal and rectal challenge. • To perform human phase I trial of microbicide combinations. • To investigate vaginal biomarkers in microbiota, immune factors and proteome analysis.

  3. ssRNA BINDING INHIBITORS REVERSE TRANSCRIPTASE INHIBITORS INTEGRASE INHIBITORS dsDNA TRANSCRIPTION + TRANSLATION HIV life CyclePotentialtargetsfor microbicides FUSIONINHIBITORS HIV CD-4 CCR-5 PROTEASE INHIIBITORS TARGET CELL ITM – Y. Van Herrewege

  4. New inhibitors in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates (ANP) 3) Inhibitors of integrase process: e.g. INSTI: RDS and MAS compounds inhibitors of LEDGF (LEDGIN) 4) Others and combinations

  5. miniCD4 proteins or CD4 mimetics(Loic Martin, CEA) Morellato-Castilloet al., 2013, J MedChem

  6. M48U1 protectsmacaquesagainstvaginalchallengewith SHIV162 mCD4 M48-U1 applied in a HEC gel 1 hour before high dose SHIV challenge → 5 out of 6 animals protected Dereuddre-Bosquet et al., 2012, PLoSPath

  7. M48U1 CD4 miniprotein as a potentialmicrobicide • Has a broad spectrum activity against HIV-1 • Protects macaques against a high dose SHIV challenge • No toxicity • Chemically stable → Needs to be combined with another (entry)inhibitor e.g. linked to CCR5 inhibitor (ongoing).

  8. Compoundsunderdevelopment in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates (ANP) 3) Inhibitors of integrase process: e.g. INSTI: RDS and MAS compounds inhibitors of LEDGF (LEDGIN) 4) Others and combinations

  9. Llama heavy chain VHH as entry inhibitors(Lucy Rutten and Theo Verrips, University of Utrecht) • Set-up: • Extensively immunize a llama with HIV gp120 or gp140 • Construct a phage library of VHH • Either perform selection on gp120 binding • Or directly in vitro test of HIV neutralization

  10. VHH as superior entry inhibitors? • Target various areas on gp120 and gp41 • Some (J3, 2E7) have a very broad spectrum against HIV-1 /SHIV • Non toxic • Chemically stable • “Synergistic” biheads = combination of entry inhibitors

  11. Compoundsunderdevelopment in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates (ANP) 3) Inhibitors of integrase process: e.g. INSTI: RDS and MAS compounds inhibitors of LEDGF (LEDGIN) 4) Others and combinations

  12. Binding and action of Nucleoside andNon-Nucleoside -RTI • N-RTI bind in polymerase site and act as chain-terminators • NN-RTI bind near polymerase site and act as allosteric inhibitors

  13. NovelNNRTI: Diaryl pyrimidines anddiaryltriazines(Koen Augustyns, Jurgen Joossens, VenkatrajMuthusamyUniversity of Antwerp) DATA DAPY Ariën et al., JAC (2013) 68: 2038-47

  14. New DATA: NNRTI formicrobicide? The new CyanovinylTriazine NNRTI 1398 • Has a better selectivity profile than Dapivirine • Is active against Dapivirine-resistant mutants = second generation NNRTI microbicide, when DPV resistance occurs? → pharmacokinetic studies in macaques ongoing

  15. Compoundsunderdevelopment in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates (ANP) 3) Inhibitors of integrase process: e.g. INSTI: RDS and MAS compounds inhibitors of LEDGF (LEDGIN) 4) Others and combinations

  16. Acyclic nucleoside phosphonates (ANPs) with dual-triple action(Jan Balzarini and Dominique Schols, REGA Institute) = 6-PhosphonylMethoxyethoxy-2,4- DiaminoPyrimidine Tobecomparedwith Balzarini et al PLOS Pathogens 2013 e1003456

  17. Compare anti-HIV and anti- HSV of ANPs Acyclovir is selectively active against HSV-1 and -2 Tenofovir is much more active against HIV-1 and -2 than against HSV; yet showed anti-HSV activity in CAPRISA trial PMEO and PMEA are active against both HIV-1 and -2 and HSV-1 and HSV-2 Balzarini et al PLOS Pathogens 2013 e1003456

  18. PMEODapym: triple action? • Directly active against HIV-1 and HIV-2 (similar to Adefovir and Tenofovir) • Possible indirect actions on HIV acquisition: • Blocking HSV (similar to Adefovir) • Stimulating β chemokines and downregulation CCR5 (selective for PMEODapym) Balzarini et al PLOS Pathogens 2013 e1003456

  19. Compoundsunderdevelopment in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates(ANP) 3) Inhibitors of integrase process: • New Integrase strand transfer inhibitors (INSTI) RDS and MAS compounds: active against Raltegravir-resistant mutants • Inhibitors of LEDGF (LEDGIN) 4) Others and combinations

  20. Lens Epithelium-DerivedGrowth Factor (LEDGF p75)may assist in various aspect of HIV integration Integrase Integrase Suzuki and CraigieNature Reviews Microbiology5, 187–196 (March 2007)

  21. LEDGINs: a new perspective for integrase inhibition Mechanism of action different from INSTI → active against INSTI resistant mutants → potentially synergistic with INSTI

  22. Compoundsunderdevelopment in CHAARM 1) Entry-fusion inhibitors: e.g. CD4 miniproteins llama single chain Ab (VHH) 2) Reverse transcriptase inhibitors: e.g. NNRTI: Di-Aryl TriAzine (DATA) NRTI: acyclic nucleoside phosphonates (ANP) 3) Inhibitors of integrase process: e.g. INSTI: RDS and MAS compounds inhibitors of LEDGF (LEDGIN) 4) Others: • Entry- fusion: NBD-basedCD4 BS inhibitors (Botta, Sienna) 5P12 RANTES (Hartley, Geneva) Small CCR5 inhibitors (Spoluka, Ukrainia) Gold nanoparticles (Penades, Bilboa) • NNRTI: N-DABO analogues (Botta, Sienna) • Proteasomeand Protease inhibitors (Spetz, Stockholm) • Combinations: first tobetested: Dapivirine – Darunavir in ring format

  23. Conclusionsandperspectives CHAARM • Novel compounds under development: • Various parts in life cycle (including new targets e.g. VHH and LEDGin) • Various chemical nature (small molecules, proteins…) • Improving selectivity index • Some active against first generation mutants (e.g. DATA 1398, MAS and RDS INSTI) • Some have intrinsic dual activity (e.g. VHH biheads, ANP)

  24. Conclusionsandperspectives CHAARM • Novel compounds under development: • Various parts in life cycle (including new targets e.g. VHH and LEDGF) • Various chemical nature (small molecules, proteins…) • Improving selectivity index • Active against mutants, resistant to existing drugs (e.g. DATA, INSTI) • Some have dual activity (e.g. VHH biheads, ANP) • Three in vitro test platform ( Carlos III, Imperial College, ITM) • Combinations-coformulations: both gels and rings (Queens, KULeuven) • Vaginal and rectal macaque PK and challenge (CEA, Paris) • Clinical Phase I trial platform and biomarker studies (ITM and U York) • Integration with biotech companies (Janssen, Particle Sciences, Spoluka…) • PPP (International Partnership on Microbicides IPM) and community (EATG)

  25. Acknowledgmentstoall CHAARM partners

  26. An extended European family enjoying life in “Golfo Paradiso” (2013 CHAARM consortium meeting in Camogli, Italy) http://chaarm.eu/ gvanham@itg.be

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