Sensitivity of a novel translocation defective reverse transcriptase inhibitor, EFdA in comparison to second generation NNRTI, Etravirine and Rilpivirines on diverse HIV-1 subtypes Duncan T. Njenda 1 , Leonard Rogers, 3 Shambhu G. Aralaggupe 1 Md Shanawazur Rahman, 1 Kamalendra Singh, 1,3 Stefan Sarafianos, 3 Anders Sonnerborg, 1 Ujjwal Neogi 1 1 Karolinska Institutet, Stockholm Sweden 2 Stellenbosch University, South Africa 3 University of Missouri, USA
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Sensitivity of a novel translocation defective reverse ...regist2.virology-education.com/2017/15EUHIVHEP/20_Neogi.pdfUjjwal Neogi1 1Karolinska Institutet, Stockholm Sweden 2 Stellenbosch
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Sensitivity of a novel translocation defective reverse transcriptase inhibitor, EFdA in comparison to second generation NNRTI, Etravirine and Rilpivirines on diverse HIV-1 subtypes
Duncan T. Njenda1, Leonard Rogers,3 Shambhu G. Aralaggupe1 Md Shanawazur
Rahman,1 Kamalendra Singh,1,3 Stefan Sarafianos,3 Anders Sonnerborg,1
Ujjwal Neogi1
1Karolinska Institutet, Stockholm Sweden 2 Stellenbosch University, South Africa 3University of Missouri, USA
Global Distribution of HIV-1 subtypes
Hemelaar 2012
Subtype in treatment response
Treatment response does not differs between subtypes
EFdA (4′-ethynyl-2-fluoro-2′-deoxyadenosine)
• EFdA is a nucleoside reverse transcriptase translocation inhibitor (NRTTI)
• Prolonged persistence of triphosphate form in PBMC and macrophages
• Potential for once weekly dosing
• Long-acting formulations under development
1Michailidis et al J Biol Chem 284: 35681-91; 2009 2Murphey-Corb et al AAC 56:4707-12; 2012
Zhe Li Salie, PNAS, 9274–9279, Kamalendra Singh personal communication
Tight binding
OCT (obligate chain terminator)
N site P site
EFdA-TP
Pre-translocation complex
EFdA-MP
N site
P site EFdA-MP
Translocation Defective RT Inhibitor (TDRTI)
DCT (Delayed chain terminator)
HIV RT
Post-translocation complex
N site
P site
115
160
184
185
114
EFdA-MP
183
Enhanced Misincorporation T/PEFdA-MP
T/PEFdA-MP+dTMP
Time (min)
More likely at OCT sites
Mode of action is sequence dependent
Decreased excision
Aim
To evaluate the virological and biochemical inhibitory potentials of EFdA
against a broad spectrum of subtype-specific viruses and a panel of known
reverse transcriptase inhibitor (RTI) resistant strains and compare the data
with first and second generation non-nucleoside reverse transcriptase