Herpes simplex virus type-1 (HSV-1) is a member of α-herpesviridae family, which cause contagious human infections. The marine habitat is a rich source of structurally unique bioactive secondary metabolites; therefore, a small library of marine natural product classes has been screened to discover a new hit entity active against HSV-1. Manzamine A (1) showed the most potent activity against HSV-1 via targeting the viral gene ICP0. Manzamine A is a β-carboline alkaloid isolated from the Indo-pacific sponge Acanthostrongylophora and several other species. Currently, acyclovir is the drug of choice for HSV-1 infections. Compared to 50 µM acyclovir, a 1 µM treatment of manzamine A produced potent repressive effects on viral replication and release of infectious viruses in SIRC cells. The potent anti-HSV-1 activity of manzamine A prompted a preliminary SAR study by testing multiple manzamines. These included 1) 8-hydroxymanzamine A (2), to test the effect of the C-8 hydroxy substitution at the β-carboline moiety, 2) manzamine E (3), to assess the importance of substitution at the azacyclooctane ring, and 3) ircinal A (4), to determine whether the β-carboline ring is required for the activity. Manzamine A was chemically transformed to its salt forms, manzamine A monohydrochloride (5) and manzamine A monotartarate (6), to test whether or not improving water solubility and hydrophilicity would positively affect the activity. Compounds were tested for activity against HSV-1 using fluorescent microscopy and plaque assay. The results showed reduced anti-HSV-1 activity of 2, suggesting that C-8 hydroxy substitution might adversely affect the activity. Similarly, manzamines 3 and 4 showed no activity against HSV-1, indicating the preference of the unsubstituted azacylcooctane and β-carboline rings, respectively, to the activity. Anti-HSV-1 activity was significantly improved for the manzamine A salts 5 and 6, suggesting that improving the overall water solubility as salt forms can significantly enhance the activity. The manzamine entity has a significant potential for development of future anti-HSV-1 drugs.

Marine natural product manzamines as novel Herpes simplex virus Type-1 inhibitors

255th National Meeting (2018)

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