New lenacapavir analogs overcome M66I resistance in HIV-1 while improving rat plasma exposure over the parent drug
- Lenacapavir analogs carrying a distinctive R2 group, designed against the structural basis of M66I capsid resistance, were made via a newly developed route.
- They stayed strongly active against wild-type virus and the M66I mutant that lenacapavir cannot inhibit.
- Lead 3S beat lenacapavir on wild-type potency, a thermal shift assay supported mutant-capsid engagement, and rat IV exposure was higher while the long half-life was largely kept.
💡 Points Based on the abstract
Thermal shift is only a binding proxy; a co-crystal or cryo-EM structure of the M66I capsid with 3S would show whether R2 really fills the pocket the mutation reshapes. Lenacapavir is already large and heavily halogenated, so the synthetic burden and lipophilicity cost of the new R2 matter, as does whether the higher IV exposure survives subcutaneous dosing.
📄 Paper · Angewandte Chemie International Edition ↗ Breakthrough Design of Highly Potent Antivirals Against Wild‐Type HIV‐1 and Lenacapavir‐Resistant M66I Variant