The discovery and design of novel HIV-1 capsid modulators and future perspectives

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.