# Harziachalasins A–G, polycyclic-fused cytochalasins from the endophytic fungus Trichoderma harzianum MLJ-4 with HIV latency reversal activity

## TL;DR

Scientists discovered seven new compounds from a fungus that can help reverse HIV latency, potentially leading to better treatments.

## Contribution

The discovery of seven new polycyclic-fused cytochalasins with HIV latency reversal activity from an endophytic fungus.

## Key findings

- Compound 4 showed strong HIV latency reversal activity with EC50 values of 2.68 μM and 2.99 μM.
- Compound 4 activates the NF-κB pathway to reverse HIV latency.
- The study provides insights into new therapeutic strategies targeting the NF-κB pathway for HIV treatment.

## Abstract

Seven new polycyclic-fused cytochalasins (CYTs), harziachalasins A–G (1–7), together with three known analogues (8–10) were isolated from the solid culture of the endophytic fungus Trichoderma harzianum MLJ-4, which was originally isolated from the leaves of Asclepias curassavica. The planar and absolute structures of all new compounds were determined on the basis of extensive spectroscopic data (1D, 2D NMR and HR-ESI–MS), NMR calculations with DP4 + probability analysis, and theoretical simulations of ECD spectra. Compound 1 represents the first example of 5/6/6 tricyclic CYT featuring a 2-methyl-4-oxopentyl side chain at the C-14 position. This novel architecture originates from a 5/6/6/7 tetracyclic CYT precursor through sequential oxidative cleavage of the C-19–C-20 bond followed by decarboxylative elimination of C-19. Compound 2 features an unprecedented 5/6/6/6/7 pentacyclic scaffold incorporating a 1,3-dioxane moiety, may be constructed by the acetalization of the 7-OH and 13-OH on a 5/6/6/7 tetracyclic CYT with acetaldehyde. Compounds 1–10 were screened for HIV latency reversal activity using J-Lat A72 and J-Lat 10.6 cell models. Compound 4 showed strong activity, with half-maximal effective concentrations (EC50) values of 2.68 μM (J-Lat A72 cells) and 2.99 μM (J-Lat 10.6 cells), demonstrating consistent potency. Mechanistic studies revealed 4 activated the NF-κB pathway to reverse HIV latency, offering insights for new therapeutic strategies targeting this pathway.

The online version contains supplementary material available at 10.1007/s13659-025-00572-1.