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Discovery of MK-8527, a long-acting HIV nucleoside reverse transcriptase translocation inhibitor
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CROI 2024 March 3-6 Denver
Izzat T. Raheem; Kerry Fillgrove; Gregory O’Donnell; Jonathan Patteson; Shih Lin Goh; Carolyn Bahnck-Teets; Qian Huang; Ernest Asante-Appiah; Min Xu; Steve S. Carroll; Jay A. Grobler; Jeffrey Hale; Ming-Tain Lai; Vinay Girijavallabhan; Tracy L. Diamond
Merck & Co., Inc., Rahway, NJ, USA
Abstract
Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) such as islatravir (ISL) are potent inhibitors of HIV-1 replication. We have invented a novel NRTTI with antiviral potency and pharmacokinetics (PK) suitable for less-frequent-than-daily dosing, an attractive profile for HIV pre-exposure prophylaxis. MK-8527 is a 7-deaza-deoxyadenosine analog and is phosphorylated intracellularly to its active triphosphate (TP) form, which is a potent inhibitor of HIV-1 replication.
MK-8527 was discovered through a lead optimization campaign focused on identifying structurally and functionally novel NRTTIs with the potential for extended-duration dosing. The mechanism of MK-8527-TP was evaluated in primer extension and footprinting assays, and antiviral activity and persistence after washout were measured in cell-based assays. PK parameters were evaluated in rats and Rhesus monkeys. Off-target activity was assessed against human DNA polymerases and in a panel of 114 enzyme/receptor binding assays.
Systematic evaluation of key positions around the nucleoside core confirmed steep SAR associated with this compound class, particularly at the 2', 3', and 4' positions. Nucleobase modifications were tolerated, and a thorough evaluation of this and other positions led to the discovery of MK-8527. MK-8527-TP inhibits reverse transcriptase by immediate (translocation) and delayed chain termination. MK-8527 has comparable antiviral activity (human PBMC IC50 = 0.21 µM) and persistence of antiviral effect after washout to ISL. The PK of MK-8527 in rats and monkeys was characterized by low to moderate clearance and volume of distribution, with good oral absorption . Following oral administration of MK-8527 to monkeys, the TP had an intracellular half-life (t1/2) in PBMCs (~48 h), significantly longer than the plasma t1/2 of the parent, MK-8527 (~7 h), as observed with other nucleos(t)ide analogs. MK-8527-TP displayed IC50 values of ≥95 µM against the human DNA polymerases tested. Neither MK-8527 nor MK-8527-TP exhibited off-target activities at 10 μM in the panel of enzyme/receptor binding assays tested.
The subnanomolar potency, absence of off-target activity, and suitable PK for at least once-weekly dosing make MK-8527 an attractive clinical candidate for prophylaxis of HIV-1 infection
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