Fullerene (C₆₀ &amp; C₇₀)‐<i>Meso</i>‐Tris‐4‐Carboxyphenyl Porphyrin Dyads Inhibit Entry of Wild‐Type and Drug‐Resistant HIV‐1 Clades B and C

The biological applications of noncationic porphyrin-fullerene (P-F) dyads as anti-HIV agents have been limited despite the established use of several cationic P-F dyads as anti-cancer photodynamic therapy (PDT) agents. This article explores the potential of amphiphilic non-cationic porphyrin-fullerene dyads as HIV-1 inhibitors under both PDT (light-treated) and non-PDT (dark) conditions. The amphiphilic P-F dyads, PB₃C₆₀ and PB₃C₇₀, demonstrated enhanced efficacy in inhibiting the entry and production of HIV-1 (subtypes B and C). Under light-harvested conditions, the dyads exhibited potent inhibitory effects (EC₅₀ for PB₃C₆₀ and PB₃C₇₀ < 10 nM) and also maintained significant inhibition under non-PDT conditions (EC₅₀ for PB₃C₆₀ = 1.43 μM and PB₃C₇₀ = 1.50 μM), while displaying notably reduced toxicity compared to their water-soluble porphyrin precursor. The P-F dyads exhibited substantial efficacy in neutralizing the T20-resistant strain 9491, both at the entry and postentry phases, thereby addressing the challenge of drug resistance.