Human viral pathogens are the main causative agents of pneumonia and bronchiolitis in infants and children, posing a large socioeconomic disease burden, associated with a high death toll. Among them, human metapneumovirus (HMPV) has been recently recognised as a leading cause of respiratory disease. The populations most at risk for developing severe HMPV-associated disease are young children, the elderly, and immunocompromised people. Mortality rates in these susceptible groups, especially in immunocompromised individuals, can be as high as 10%. Currently, there is neither vaccine nor drug therapy available to prevent or treat HMPV infection. Human metapneumoviruses are decorated with three surface glycoproteins: fusion protein (F), attachment protein (G), and small hydrophobic protein (SH). The F protein plays important key roles during various stages of the HMPV lifecycle such as recognition and binding to host cell receptor, fusion of virus envelope with host cell membrane, and cell to cell membrane fusion. As a result, the F protein is considered as a promising target for antiviral drug discovery. However, little is known about the interaction between HMPV F and its host cell surface receptors, except for heparan sulfate, a glycosaminoglycan which has been proposed to act as the initial receptor. In this thesis, we first aim to contribute to the discovery of HMPV therapeutics by identifying approved drugs that may be rapidly repurposed as anti-HMPV agents. Next, we aim to fill the knowledge gap related to HMPV F and its host cellular receptors, with a focus on glycoreceptors, as heparan sulfate has been described as the primary host attachment factor. Lastly, we aimed to build a drug discovery toolkit including two highly valuable models that can be used for further rational drug design and early-stage preclinical drug candidate evaluation. In this thesis we present the discovery of novel anti- HMPV inhibitors and provide relevant models for future drug development.