Dolutegravir Mechanism of Action
Dolutegravir inhibits HIV-1 integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle. 1
Molecular Mechanism
- Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI) that binds directly to the HIV-1 integrase enzyme's active site 1, 2
- It specifically blocks the strand transfer integration step, preventing viral DNA from being incorporated into the host cell's genome 1, 3
- In biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA, dolutegravir demonstrated IC₅₀ values of 2.7 nM and 12.6 nM 1
Antiviral Potency
- Dolutegravir exhibits potent antiviral activity against wild-type HIV-1 with mean EC₅₀ values ranging from 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells and MT-4 cells 1
- Against 13 clinically diverse clade B isolates, dolutegravir demonstrated a mean EC₅₀ value of 0.52 nM 1
- The drug maintains activity across diverse HIV-1 clades (A through G and group O) with EC₅₀ values ranging from 0.02 nM to 2.14 nM 1
- Dolutegravir also demonstrates activity against HIV-2 clinical isolates with EC₅₀ values ranging from 0.09 nM to 0.61 nM 1
Unique Pharmacodynamic Properties
- The binding half-life and potential of dolutegravir at the integrase active site are far superior to first-generation INSTIs (raltegravir and elvitegravir), conferring a uniquely high genetic barrier to resistance 2, 4
- The slow dissociation rate from the integrase complex, combined with high plasma inhibition quotient and long plasma half-life, prevents resistance development even in treatment-experienced patients 4
- Dolutegravir maintains concentrations far above those effective against wild-type viruses throughout the dosing interval, allowing once-daily administration 2, 5
Clinical Resistance Profile
- In pivotal phase III studies of treatment-naïve patients (SPRING-2 and SINGLE trials), none of 1,118 individuals developed resistance-associated mutations at integrase or reverse transcriptase through 96-144 weeks of treatment 1, 4
- When resistance does emerge (primarily R263K mutation), it induces a significant fitness cost that prevents HIV-1 from evading drug pressure and blocks accumulation of compensatory mutations 4
- This evolutionary pathway leads to a dead-end for the virus, representing a previously unrecognized mechanism of maintaining viral suppression despite treatment failure 4
Mechanism Distinguishing from First-Generation INSTIs
- Unlike raltegravir, dolutegravir can be administered once daily without pharmacokinetic boosting due to its superior binding characteristics 5, 3
- The tricyclic carbamoyl pyridone analog structure of dolutegravir provides enhanced binding affinity compared to the diketo acid structure of raltegravir 6
- Dolutegravir retains activity against viruses harboring one or more integrase mutations that confer resistance to raltegravir or elvitegravir 2, 5