Curriculum: Drug Sciences

Supervisor: Rita Meleddu

Co-Supervisor: Simona Distinto

Curriculum Vitae

Laura graduated in Medicinal Chemistry and Pharmaceutical Technology (LM-13) at the University of Cagliari in May 2022, with an experimental thesis entitled “Synthesis of Potential Anticancer Agents Based on the Indolinone Nucleus”, under the supervision of Prof. Elias Maccioni and co-supervision of Prof. Florence McCarthy. As part of her thesis work, she spent five months in Prof. McCarthy’s laboratory at University College Cork, Ireland.
After graduation, she was awarded an eight-month and subsequently a one-year research fellowship at the University of Cagliari. The respective research projects focused on the “Synthesis of Potential SARS-CoV-2 Replication Inhibitors Targeting the Viral Protein Nsp13 (Helicase)”, under the supervision of Prof. Simona Distinto, and on the “Identification and Biological Evaluation of Broad-Spectrum Inhibitors of NS2B/NS3 Protease to Fight Flavivirus Outbreaks”, under the supervision of Prof. Rita Meleddu.
She is currently a PhD student in the PhD Program in Life, Environmental, and Drug Sciences (Drug Science Curriculum), under the supervision of Prof. Rita Meleddu and Prof. Simona Distinto. Her research project focuses on the identification of new antiviral, antimicrobial, and anticancer agents.

Research Topic

Design, synthesis and characterization of new potential allosteric Flavivirus NS3pro inhibitors with broad-spectrum activity

Abstract

Laura Demuru's PhD project focuses on the design and development of new allosteric inhibitors for the Flavivirus NS3 protease (NS3pro). This family of viruses, including Zika (ZIKV), West Nile (WNV), Dengue (DENV), and Yellow Fever (YFV) viruses, represents a constant threat to public health, with a notable lack of specific approved antiviral drugs. The NS3 protease (NS3pro) is a multifunctional enzyme crucial for viral replication, making it a promising target for antiviral development.

However, the development of selective active site inhibitors has been hampered by structural homology with human proteases and the limited efficacy of peptide-based compounds. To overcome these challenges, Demuru's project adopts a strategy that prioritizes the identification of allosteric inhibitors, which act on a site different from the active site or interfere with the interactions of the NS2B-NS3pro complex.

The methodology employs a combined approach of computational chemistry and organic synthesis. Molecular Dynamics simulations, Structure-Based, and Ligand-Based approaches will be used to identify new "hit" compounds in silico. Subsequently, new libraries of molecules based on the identified scaffolds will be synthesized and characterized using NMR, HRMS, and potentially X-ray diffraction.

The synthesized molecules will undergo biological evaluation against specific viral targets, in collaboration with the virology group at the University of Cagliari. The goal is to define optimal structural requirements for biological activity and optimize the compounds, including studies on ADME (Absorption, Distribution, Metabolism, Excretion) properties during a research period abroad.

Expected results include the development of inhibitors capable of acting in the nanomolar range. The discovery of broad-spectrum anti-Flavivirus molecules (pan-flavivirus) could have a significant impact on antiviral therapy, given the urgent need for new therapeutic options against these emerging and re-emerging viral infections.

Tutoring Activities

> Analisi dei Farmaci II: 1st semester A.Y. 2024-2025, Prof. Elias Maccioni

> Analisi dei Medicinali II: 1st semester A.Y. 2024-2025, Prof. Filippo Cottiglia, Prof. Rita Meleddu

> Analisi dei Farmaci II: 1st and 2nd semester A.Y. 2023-2024, Prof. Elias Maccioni

> Analisi dei Medicinali II: 1st semester A.Y. 2023-2024, Prof. Filippo Cottiglia, Prof. Rita Meleddu

Publications

IRIS: https://iris.unica.it/cris/rp/rp34801

ORCID: https://orcid.org/0009-0006-2424-3789

Conference Contributions

> Demuru L., Lupia A., Sanna E., Onali A., Atzeni G., Cottiglia F., Distinto S., Maccioni E., Meleddu R. Application of Computational Methods for the Identification of ZIKV NS3pro Potential Allosteric Inhibitors. Flash Poster Presentation at XIII Paul Ehrlich Euro-PhD Network & OneHealthdrugs COST Action.

> Demuru L., Lupia A., Sanna E., Onali A., Atzeni G., Cottiglia F., Distinto S., Maccioni E., Meleddu R. Flash Poster Presentation at XIII Paul Ehrlich Euro-PhD Network & OneHealthdrugs COST Action “Application of Computational Methods for the Identification of ZIKV NS3pro Potential Allosteric Inhibitors”. 

> Demuru L., Lupia A., Sanna E., Onali A., Atzeni G., Cottiglia F., Distinto S., Maccioni E., Meleddu R. Poster Presentation at 7th-Innovative Approaches for Antiviral Agents Summer School (IAAASS) “Exploring the structural features for the identification of ZIKV NS3pro allosteric inhibitors”.

> Demuru L., Lupia A., Nieddu S., Esposito F., Tramontano E., Distinto S., Sanna E., Onali A., Atzeni G., Cottiglia F., Grandi N., Corona A., Maccioni E., Meleddu R. Flash Poster Presentation at Next Generation Chemists 24. “In silico approaches to uncover allosteric inhibitors of ZIKV NS3pro”.

> Demuru L., Lupia A., Nieddu S., Emmolo R., Paulis A., Esposito F., Distinto S., Bryant S.D., Onali A., Sanna E., Atzeni G., Cottiglia F., Grandi N., Corona A., Tramontano E., Maccioni E., Meleddu R. Poster Presentation at Third Light Retreat DiSVA “ A combined computational and biochemical approach for the identification of ZIKV NS3pro potential allosteric inhibitors”.

> Demuru L., Lupia A., Nieddu S., Emmolo R., Paulis A., Esposito F., Distinto S., Bryant S.D., Onali A., Sanna E., Atzeni G., Cottiglia F., Grandi N., Corona A., Tramontano E., Maccioni E., Meleddu R. Flash Poster Presentation at GP2A 2025 – Paul Ehrlich MedChem 2025 – COST Action OneHealthdrugs. “Identifying potential allosteric inhibitors of ZIKV NS3pro through a combined computational and biochemical approach”.