Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV‑1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2014-03, Vol.77 (3), p.618-624
• Main Authors: Mejia, Eric J, Loveridge, Steven T, Stepan, George, Tsai, Angela, Jones, Gregg S, Barnes, Tiffany, White, Kimberly N, Drašković, Marija, Tenney, Karen, Tsiang, Manuel, Geleziunas, Romas, Cihlar, Tomas, Pagratis, Nikos, Tian, Yang, Yu, Helen, Crews, Phillip
• Format: Article
• Language: English
• Subjects: Ascomycota - chemistry; Biological Products - chemistry; Biological Products - pharmacology; CD4-Positive T-Lymphocytes - virology; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; HIV Infections - virology; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; Humicola fuscoatra; Lactones - chemistry; Lactones - pharmacology; Macrolides - chemistry; Macrolides - pharmacology; Marine Biology; Models, Biological; Molecular Structure; Virus Latency - drug effects
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np400889x

An extract of Humicola fuscoatra (UCSC strain no. 108111A) was shown to reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. We report the bioassay-guided isolation and structure determination of several resorcyclic acid lactones, including four known compounds, radicicol (1, aka. monorden) and pochonins B (2), C (3), and N (4), and three new analogues, radicicols B–D (5–7). Compounds 1–3 and 5 showed moderate activities in the memory T cell model of HIV-1 latency. Radicicol (1) displayed lower potency in reactivating latent HIV-1 (EC50 = 9.1 μM) relative to the HDAC inhibitors apicidin (EC50 = 0.3 μM), romidepsin (EC50 = 0.003 μM), and SAHA (EC50 = 0.6 μM); however, it achieved equivalent maximum efficacy relative to the positive control compounds (98% of SAHA and romidepsin).