an integrated european effort to develop vaginal/rectal hiv preventive drugs
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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 - PowerPoint PPT PresentationTRANSCRIPT
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www.chaarm.eu
An integrated European effort to develop vaginal/rectal HIV preventive drugs
Guido Vanham and Kevin Ariën,Virology Unit,
Institute of Tropical Medicine, Antwerp
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CHAARM: objectives
1) To develop new HIV antivirals for vaginal/rectal HIV prevention
2) To develop microbicide combinations and coformulations
3) To test efficacy of microbicide (combinations) in macaque models of vaginal and rectal challenge.
4) To perform human phase I trial of microbicide combinations.
5) To investigate vaginal biomarkers in microbiota, immune factors and proteome analysis.
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HIV life CyclePotential targets for microbicides
TRANSCRIPTION +TRANSLATION
REVERSETRANSCRIPTASE
INHIBITORS
BINDINGINHIBITOR
S
FUSIONINHIBITORS
INTEGRASEINHIBITORS
ssRNA
dsDNA
HIV
TARGETCELL
CD-4CCR-5
PROTEASE INHIIBITORS
ITM – Y. Van Herrewege
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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 compoundsinhibitors of LEDGF (LEDGIN)
4) Others and combinations
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miniCD4 proteins or CD4 mimetics(Loic Martin, CEA)
Morellato-Castillo et al., 2013, J Med Chem
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M48U1 protects macaques against vaginal challenge with SHIV162
Dereuddre-Bosquet et al., 2012, PLoS Path
mCD4 M48-U1 applied in a HEC gel 1 hour before high dose SHIV challenge→ 5 out of 6 animals protected
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M48U1 CD4 miniprotein as a potential microbicide
− 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).
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Compounds under development 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 compoundsinhibitors of LEDGF (LEDGIN)
4) Others and combinations
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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
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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
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Compounds under development 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 compoundsinhibitors of LEDGF (LEDGIN)
4) Others and combinations
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Binding and action of Nucleoside and Non-Nucleoside -RTI
- N-RTI bind in polymerase site and act as chain-terminators- NN-RTI bind near polymerase site and act as allosteric inhibitors
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Novel NNRTI: Diaryl pyrimidines and diaryl triazines(Koen Augustyns, Jurgen Joossens, Venkatraj Muthusamy
University of Antwerp)
N
NHN NH
CN
TMC120(Dapivirine)
N
NHN NH
CN
CN
TMC278(Rilpivirine)
N N
NHN NH
CN
NH2Triazine
(UAMC-00522)
N N
NHN NH
NH2
CN
CN
Cyanovinyltriazine(UAMC-01398)
DAPY DATA
Ariën et al., JAC (2013) 68: 2038-47
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New DATA: NNRTI for microbicide?
The new Cyanovinyl Triazine 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
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Compounds under development 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 compoundsinhibitors of LEDGF (LEDGIN)
4) Others and combinations
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Acyclic nucleoside phosphonates (ANPs) with dual-triple action(Jan Balzarini and Dominique Schols, REGA Institute)
Balzarini et al PLOS Pathogens 2013 e1003456
To be compared with
= 6-PhosphonylMethoxyethoxy-2,4- DiaminoPyrimidine
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Compare anti-HIV and anti- HSV of ANPs
Acyclovir is selectively active against HSV-1 and -2Tenofovir is much more active against HIV-1 and -2 than against HSV;
yet showed anti-HSV activity in CAPRISA trialPMEO and PMEA are active against both HIV-1 and -2 and HSV-1 and HSV-2
Balzarini et al PLOS Pathogens 2013 e1003456
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PMEODapym: triple action?
1) Directly active against HIV-1 and HIV-2 (similar to Adefovir and Tenofovir)
2) 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
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Compounds under development 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
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Suzuki and Craigie Nature Reviews Microbiology 5, 187–196 (March 2007)
Integrase
Integrase
Lens Epithelium-Derived Growth Factor (LEDGF p75)may assist in various aspect of HIV integration
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LEDGINs: a new perspective for integrase inhibition
Mechanism of action different from INSTI
→ active against INSTI resistant mutants→ potentially synergistic with INSTI
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Compounds under development 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 compoundsinhibitors of LEDGF (LEDGIN)
4) Others:− Entry- fusion: NBD-based CD4 BS inhibitors (Botta, Sienna)
5P12 RANTES (Hartley, Geneva)Small CCR5 inhibitors (Spoluka, Ukrainia)Gold nanoparticles (Penades, Bilboa)
− NNRTI: N-DABO analogues (Botta, Sienna)− Proteasome and Protease inhibitors (Spetz, Stockholm)− Combinations: first to be tested: Dapivirine – Darunavir in ring format
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Conclusions and perspectives CHAARM
1) 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)
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Conclusions and perspectives CHAARM
1) 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)
2) Three in vitro test platform ( Carlos III, Imperial College, ITM)3) Combinations-coformulations: both gels and rings (Queens, KULeuven)4) Vaginal and rectal macaque PK and challenge (CEA, Paris) 5) Clinical Phase I trial platform and biomarker studies (ITM and U York)6) Integration with biotech companies (Janssen, Particle Sciences, Spoluka…) 7) PPP (International Partnership on Microbicides IPM) and community (EATG)
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Acknowledgments to all CHAARM partners
Charles Kelly, KCL, UK, coordinatorGary Coulton, SGUL, UKRoger Le Grand and Loic Martin, CEA, FRGuido Vanham, Vicky Jespers, ITM, BEKoen Augustyns, UA, BEKarl Malcolm, QUB, UKStephan Grzesiek, Biozentrum, CHGianni Pozzi and Maurizio Botta, UNISI, ITPatrick Augustyns, Zeger Debyser, Dominique Schols, Jan Balzarini, KUL, BERobin Weiss, UCL, UKLuca Vangelista, Elisa Vicenzi, FCSR, ITCharles Lacey, UoY, UKTheo Verrips/Lucy Rutten, UU-Bio, NLPepe Alcami, ISCIII, ESSoledad Penades, CICbiomaGUNE, ESRachel Chikwamba, CSIR, ZA
Roberto Di Santo, UNIROMA, ITVasily Pinchuk, Spoluka, UAHinano Spreafico, MINERVA, BEDietmar Katinger, Polymun, ATJames Rooney, Gilead, USMark Mitchnick, Particle Sciences, USOliver Hartley, UGE, CHBrid Devlin, IPM, USAnna Lena Spetz, KI, SEGuy Cairns, EATG, BERobin Offord, Mintaka, CHJens Van Roey, Tibotec-Virco Virology, BECaterina Ciabattini, MBT, ITIvan Roitt, MU, UKRobin Shattock, IC, UKJanneke Van der Wijgert, U Liv, UK
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An extended European family enjoying life in “Golfo Paradiso” (2013 CHAARM consortium meeting in Camogli, Italy)
http://chaarm.eu/[email protected]