The challenge of HTLV-1 therapeutics: lessons from anti-protease approaches

The human T-cell leukaemia virus type 1 (HTLV-1) is an oncogenic retrovirus responsible for severe diseases, including adult T-cell leukaemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite its significant global prevalence, specific direct-acting antiviral therapies remain unavailable. This review comprehensively surveys the HTLV-1 protease (HTLV-1 PR), a pivotal homodimeric aspartic protease essential for viral maturation and infectivity, as a critical antiviral drug target.​ A detailed analysis of HTLV-1 PR's narrow substrate specificity, influenced by specific subsite interactions, highlights its distinction from the human immunodeficiency virus-1 protease (HIV-1 PR) and explains the limited efficacy of cross-targeting existing HIV-1 inhibitors. The review critically assesses current inhibitor development strategies, including the challenges posed by its unique structural architecture and the need for novel, HTLV-1-specific chemical scaffolds. We discuss the promise of structure-based drug design, in silico screening, and combinatorial chemistry in overcoming these hurdles, aiming to accelerate the discovery of potent and selective HTLV-1 PR inhibitors. This work consolidates knowledge on HTLV-1 PR, identifies key challenges, and proposes future research directions, ultimately contributing to the urgent need for effective therapeutic interventions against HTLV-1 infection.