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The SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants of the virus is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against Covid-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here we exploited the enormous potential of plant metabolism, in particular the bryophyte Marchantia polymorpha, and following a bioactivity-guided fractionation and mass-spectrometry approach, identified a potent SARS-CoV-2 antiviral. We found that the chlorophyll derivative Pheophorbide a (PheoA), a natural porphyrin similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2 preventing infection of cultured monkey and human cells, without noticeable citotoxicity. We also show that PheoA prevents coronavirus entry into the cells by directly targeting the viral particle. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against (+)strand RNA viral pathogens such as HCV, West Nile, and other coronaviruses, but not against (-)strand RNA viruses, such as VSV. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, and suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2. Moreover, PheoA adds to remdesivir's efficiency and is currently employed in photoactivable cancer therapies in humans., This research was funded by CSIC (PIE-RD-COVID-19 ref 202040E236 to R.S., PIE-RD COVID-19 ref. E202020E079 to P.G and U.G, and CSIC-CoV19-153 ref PIE-202080E221 to M.G-R.). Funding from EVA (European Virus Archive; grant agreement No 871029) is gratefully acknowledge. GH. J-A. was supported by the Deutsche Forschungsgemeinschaft (Individual Research Grant JI 241/2-1).

Summary The interplay between the phytohormone abscisic acid (ABA) and the gasotransmitter nitric oxide (NO) regulates seed germination and post-germinative seedling growth. We show that GAP1 (germination in ABA and cPTIO 1) encodes the transcription factor ANAC089 with a critical membrane-bound domain and extranuclear localization. ANAC089 mutants lacking the membrane-tethered domain display insensitivity to ABA, salt, and osmotic and cold stresses, revealing a repressor function. Whole-genome transcriptional profiling and DNA-binding specificity reveals that ANAC089 regulates ABA- and redox-related genes. ANAC089 truncated mutants exhibit higher NO and lower ROS and ABA endogenous levels, alongside an altered thiol and disulfide homeostasis. Consistently, translocation of ANAC089 to the nucleus is directed by changes in cellular redox status after treatments with NO scavengers and redox-related compounds. Our results reveal ANAC089 to be a master regulator modulating redox homeostasis and NO levels, able to repress ABA synthesis and signaling during Arabidopsis seed germination and abiotic stress., Graphical abstract, Highlights • GAP1 encodes transcription factor ANAC089, expressed in seeds and stress • Changes in cellular redox status induce translocation of ANAC089 to the nucleus • ANAC089 binds specifically to genes controlling seed germination and abiotic stress • ANAC089 regulates NO levels and cell redox and represses ABA synthesis and signaling, Albertos et al. report the cleavage of ANAC089 transcription factor from the membrane-anchoring domain in the endoplasmic reticulum, controlled by cell redox alterations. Once in the nucleus, ANAC089 induces redox homeostasis-related genes and represses ABA-responsive genes to increase NO levels and ABA insensitivity during seed germination and abiotic stress.

Changes in light quality indicative of competition for this essential resource influence plant growth and developmental transitions; however, little is known about neighbor proximity-induced acceleration of reproduction. Phytochrome B (phyB) senses light cues from plant competitors, ultimately leading to the expression of the floral inducers FLOWERING LOCUS T (FT) and TWIN SISTER of FT (TSF). Here we show that PHYTOCHROME INTERACTING FACTORs 4, 5 and 7 (PIF4, PIF5 and PIF7) mediate neighbor proximity-induced flowering, with PIF7 playing a prominent role. These transcriptional regulators act directly downstream of phyB to promote expression of FT and TSF. Neighbor proximity enhances PIF accumulation towards the end of the day, coinciding with enhanced floral inducer expression. We present evidence supporting direct PIF-regulated TSF expression. The relevance of our findings is illustrated by the prior identification of FT, TSF and PIF4 as loci underlying flowering time regulation in natural conditions., In plants, phytochrome B senses light cues indicative of neighbouring competitors leading to accelerated flowering. Here the authors show that PHYTOCHROME INTERACTING FACTORs 4, 5 and 7 (PIF4, PIF5 and PIF7) mediate neighbor proximity-induced flowering acting downstream of phyB to promote expression of FT and TSF.