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

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).

[1]  C. Spina,et al.  Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing , 2014, PLoS pathogens.

[2]  R. Siliciano,et al.  Targeting HIV latency: pharmacologic strategies toward eradication. , 2013, Drug discovery today.

[3]  J. Eron,et al.  Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy , 2012, Nature.

[4]  Kyria Boundy-Mills,et al.  Natural product libraries to accelerate the high-throughput discovery of therapeutic leads. , 2011, Journal of natural products.

[5]  I. Sadowski,et al.  The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV‐1 without producing a T cell response , 2011, FEBS letters.

[6]  H. Ying,et al.  HIV-1 reactivation induced by apicidin involves histone modification in latently infected cells. , 2011, Current HIV research.

[7]  J. Mellors,et al.  Inhibitors of Histone Deacetylases , 2011, The Journal of Biological Chemistry.

[8]  A. Ikeda,et al.  Synthesis and structure-activity relationships of radicicol derivatives and WNT-5A expression inhibitory activity. , 2009, Bioorganic & medicinal chemistry.

[9]  A. Ikeda,et al.  Pochonins K–P: new radicicol analogues from Pochonia chlamydosporia var. chlamydosporia and their WNT-5A expression inhibitory activities , 2009 .

[10]  Alberto Bosque,et al.  Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. , 2009, Blood.

[11]  J. Mellors,et al.  Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy , 2008, Proceedings of the National Academy of Sciences.

[12]  S. Barluenga,et al.  Solution- and solid-phase synthesis of radicicol (monorden) and pochonin C. , 2005, Chemistry.

[13]  Vincent Zoete,et al.  Design, synthesis, and biological evaluation of HSP90 inhibitors based on conformational analysis of radicicol and its analogues. , 2005, Journal of the American Chemical Society.

[14]  Anke Mayer-Bartschmid,et al.  Pochonins A-F, new antiviral and antiparasitic resorcylic acid lactones from Pochonia chlamydosporia var. catenulata. , 2003, Journal of natural products.

[15]  R. Siliciano,et al.  Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells , 2003, Nature Medicine.

[16]  Phillip Crews,et al.  Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. , 2003, The Journal of organic chemistry.

[17]  S. Akinaga,et al.  Halohydrin and oxime derivatives of radicicol: synthesis and antitumor activities. , 2002, Bioorganic & medicinal chemistry.

[18]  Y. Korin,et al.  Effects of Prostratin on T-Cell Activation and Human Immunodeficiency Virus Latency , 2002, Journal of Virology.

[19]  V. Soriano,et al.  Different degree of immune recovery using antiretroviral regimens with protease inhibitors or non-nucleosides , 2002, AIDS.

[20]  R. Siliciano,et al.  The challenge of viral reservoirs in HIV-1 infection. , 2002, Annual review of medicine.

[21]  B. Haynes,et al.  Immune reconstitution in patients with HIV infection. , 2002, Annual review of medicine.

[22]  M. Boyd,et al.  Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. , 2001, Blood.

[23]  L. Pearl,et al.  Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. , 1999, Journal of medicinal chemistry.

[24]  S. Schreiber,et al.  Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  D. Richman,et al.  Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. , 1997, Science.

[26]  F. Evans,et al.  Isolation of Prostratin from Euphorbia cornigera. , 1985, Planta medica.

[27]  K. Nagashima,et al.  A new antifungal antibiotic, trichostatin. , 1976, The Journal of antibiotics.

[28]  K. Etŏ,et al.  [Differential assay and clinical application of ampicillin-oxacillin]. , 1971, The Japanese journal of antibiotics.

[29]  C. W. Shoppee,et al.  The constitution of radicicol , 1964 .