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, PBC and PBC, 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 (EC for PBC and PBC < 10 nM) and also maintained significant inhibition under non-PDT conditions (EC for PBC = 1.43 μM and PBC = 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.
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