Discovery of MK-8527: A Long-Acting HIV-1 Nucleoside Reverse Transcriptase Translocation Inhibitor

Background:

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.

Methods:

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.

Results:

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 (t_1/2) in PBMCs (~48 h), significantly longer than the plasma t_1/2 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.

Conclusions:

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