Viral infections pose a persistent threat to human health. The relentless epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health problem, with millions of infections and fatalities so far. Traditional approaches such as random screening and optimization of lead compounds by organic synthesis have become extremely resource- and time-consuming. Various modern innovative methods or integrated paradigms are now being applied to drug discovery for significant resistance in order to simplify the drug process. This review provides an overview of newly emerging antiviral strategies, including proteolysis targeting chimera (PROTAC), ribonuclease targeting chimera (RIBOTAC), targeted covalent inhibitors, topology-matching design and antiviral drug delivery system. This article is dedicated to Prof. Dr. Erik De Clercq, an internationally renowned expert in the antiviral drug research field, on the occasion of his 80th anniversary.

The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC₅₀ in the anti-HIV-2 assays (EC₅₀ = 4.86 ± 1.71 μM; CC₅₀= 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.

Although combination antiretroviral therapy (cART) has achieved significant success in treating HIV, the emergence of multidrug-resistant viruses and cumulative medication toxicity make it necessary to find new classes of antiretroviral agents with novel mechanisms of action. With high sequence conservation, the HIV-1 capsid (CA) protein has attracted attention as a prospective therapeutic target due to its crucial structural and regulatory functions in the HIV-1 replication cycle. Herein, the authors provide a cutting-edge overview of current advances in the design and discovery of CA modulators, PF74, GS-6207 and their derivativeswhich targets a therapeutically attractive NTD-CTD interprotomer pocket within the hexameric configuration of HIV-1 CA. The discovery and development of these compounds, and derivatives thereof, have provided valuable information for the design of second-generation CA-targeting antivirals. Despite some successes in designing and discovering HIV-1 CA modulators, more studies are required to decipher which chemical groups confer specific desirable properties. The future of CA-modulating compounds may lie in covalent inhibition and the creation of proteolysis-targeting chimeras (PROTACs). Moreover, biological interrogation of the process of CA uncoating, virus-host interactions, and studies on the lattice-binding restriction factors may improve our knowledge of HIV-1 CA and support the design of new antiviral agents.