Biology subjects

Moussa, A.

Publications and source records attributed to Moussa, A..

7 recordsLinked to original sources

bioRxiv2026

TEgment dissects transposable element reactivation upon CDK9 inhibition in acute myeloid leukemia

Cyclin-dependent kinase 9 (CDK9) inhibition represents a promising therapeutic strategy in cancers that disrupts RNA polymerase II pause release and collapses oncogenic transcripts. Here, we show that CDK9 inhibition also induces widespread transposable element (TE) activation across diverse cancer types. In acute myeloid leukemia (AML), CDK9 inhibition induces rapid epigenetic reprogramming and robust TE upregulation. To dissect this non-canonical transcriptional response, we developed TEgment, a TE-centric RNA-sequencing analysis pipeline that classifies TE expression into distinct structural modalities: standalone, readthrough, protein-coding gene-embedded (5'UTR, coding exons, and 3'UTRs), lncRNA-embedded, intron-retained, and TE-initiated/terminated transcription events. Applying TEgment to CDK9-inhibited AML revealed that TEs are predominantly expressed as readthrough, 3'UTR-embedded, and lncRNA-embedded transcripts rather than autonomous units, challenging prevailing assumptions about TE reactivation. TEgment provides a versatile framework for resolving TE transcriptional modalities at locus and structural levels, enabling precise interpretation of TE-derived transcripts in cancer and other contexts.

genomics↗

bioRxiv2025

Peripheral anatomy and central connectivity of proprioceptive sensory neurons in the Drosophila wing

Recent advances in electron microscopy (EM) and automated image segmentation have produced synaptic wiring diagrams of the Drosophila central nervous system. A limitation of existing fly connectome datasets is that most sensory neurons are excised during sample preparation, creating a gap between the central and peripheral nervous systems. Here, we bridge this gap by reconstructing wing sensory axons from the Female Adult Nerve Cord (FANC) EM dataset and mapping them to peripheral sensory structures using genetic tools and light microscopy. We confirm the location and identity of known wing mechanosensory neurons and identify previously uncharacterized axons, including a novel population of putative proprioceptors that make monosynaptic connections onto wing steering motor neurons. We also find that proprioceptors of adjacent campaniform sensilla on the wing have distinct axon morphologies and postsynaptic partners, suggesting a high degree of specialization in axon pathfinding and synaptic partner matching. The peripheral location and central projections of wing sensory neurons are stereotyped across flies, allowing this wing proprioceptor atlas and genetic toolkit to guide analysis of other fly connectome datasets.

neuroscience↗

bioRxiv2024

The activation chain of the broad-spectrum antiviral bemnifosbuvir at atomic resolution

Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5-triphosphate AT-9010, with an obligate order of reactions. AT-9010 selectively inhibits essential viral enzymes, accounting for broad spectrum antiviral potency. Functional and structural data at atomic resolution decipher N6-purine deamination compatible with metabolic activation by human ADALP1. Crystal structures of human HINT1, ADALP1, GUK1, and NDPK at 2.09, 2.44, 1.76, and 1.9 [A] resolution, respectively, with cognate precursors of AT-9010 illuminate the activation pathway from the orally available bemnifosbuvir to AT-9010, pointing to key drug-protein contacts along the activation pathway. Our work provides a framework to integrate the design of antiviral nucleotide analogues, confronting requirements and constraints associated with activation enzymes along the 5-triphosphate assembly line.

biochemistry↗

bioRxiv2023

The bacterial community of the European spruce bark beetle in space and time

The European spruce bark beetle Ips typographus is a pest causing severe damages in forests dominated by the Norway spruce in Europe. Microorganisms play an essential role in the host species performance, including nutrition, fitness as well as in overcoming host defenses. Here, we performed high-throughput 16S rRNA metabarcoding of I. typographus across different populations in Europe, to assess its bacterial community. We investigated four postglacial refugial areas in Europe and focused specifically on a current bark beetle hot spot in the Dolomites where we compared populations with different epidemiological phases (outbreaking vs. non-outbreaking) and across different seasons (pre-overwintering vs. overwintering). Our results show that the bacterial community structure varied among populations from the refugial areas and between different regions within the Dolomites. We found a significant difference in the bacterial community between pre-overwintering and overwintering individuals, but we did not find differences between epidemic and endemic populations. The prevalence of the genus Erwinia which was present in every individual and Pseudoxanthomonas in almost every individual across all populations, suggests that these taxa form the core bacterial community of I. typographus. Furthermore, several additional bacterial taxa occurred in all populations, but with variable frequencies. This study highlights a complex interaction of I. typographus and various bacterial taxa across different regions and ecological phases of I. typographus populations and provides new insights into the role of microorganisms in the biology of this important pest species.

ecology↗

bioRxiv2021

AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro, with a 50% effective concentration (EC50) of 0.31 M. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log10-fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 - 100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection. Author summaryYellow fever virus (YFV) is transmitted by mosquitoes, and its infection can lead to a lethal viral hemorrhagic fever associated with liver damage. While an effective vaccine is available, in places where the vaccination rate is low, in the event of an unexpected outbreak, or where vaccination is not recommended individually, having an effective antiviral treatment is critical. We previously reported that the nucleotide analog prodrug AT-752 potently inhibited the YFV in cultured cells. Here we showed that in hamsters infected with YFV, oral treatment with 1000 mg/kg AT-752 for 7 days reduced the production of infectious virus particles in the blood, and decreased serum alanine aminotransferase, a marker of liver damage, to levels measured in uninfected animals. In addition, at 21 days after infection, 70 - 100% of the infected animals in the treatment groups survived compared to 0% in the untreated group. Moreover, the amount of the active metabolite formed from AT-752 was highest in the livers and kidneys of the treated animals, organs that are targeted by the virus. These results suggest that AT-752 is a promising compound to develop for the treatment of YFV infection.

pharmacology and toxicology↗

bioRxiv2021

Protein-primed RNA synthesis in SARS-CoVs and structural basis for inhibition by AT-527

How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and -2 Nidovirus RdRp-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-priming mechanism reminiscent of Picornaviridae enzymes. In parallel, the RdRp active site of nsp12 synthesizes a pppGpU primer, which primes (-)ssRNA synthesis at the precise genome-poly(A) junction. The guanosine analogue 5-triphosphate AT-9010 (prodrug: AT-527) tightly binds to the NiRAN and inhibits both nsp8-labeling and the initiation of RNA synthesis. A 2.98 [A] resolution Cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-(nsp8)2 /RNA/NTP quaternary complex shows AT-9010 simultaneously binds to both NiRAN and RdRp active site of nsp12, blocking their respective activities. AT-527 is currently in phase II clinical trials, and is a potent inhibitor of SARS-CoV-1 and -2, representing a promising drug for COVID-19 treatment.

biochemistry↗

bioRxiv2020

AT-527 is a potent in vitro replication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic

AT-527, an orally administered double prodrug of a guanosine nucleotide analog, has been shown previously to be highly efficacious and well tolerated in HCV-infected subjects. Herein we report the potent in vitro activity of AT-511, the free base form of AT-527, against several coronaviruses, including SARS-CoV-2, the causative agent of COVID-19. In normal human airway epithelial (HAE) cell preparations, the average concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.5 {micro}M, very similar to the EC90 for AT-511 against HCoV-229E, HCoV-OC43 and SARS-CoV in Huh-7 cells. No cytotoxicity was observed for AT-511 in any of the antiviral assays up to the highest concentration tested (100 {micro}M). Surprisingly, AT-511 was 30-fold less active against MERS-CoV. This differential activity may provide a clue to the apparent unique mechanism of action of the guanosine triphosphate analog formed from AT-527.

pharmacology and toxicology↗