Looking for Novel Capsid Protein Multimerization Inhibitors of Feline Immunodeficiency Virus

Abstract

Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses. It causes acquired immunodeficiency syndrome (AIDS) in worldwide domestic and non-domestic cats and is a cause of an important veterinary issue. The genome organization of FIV and the clinical characteristics of the disease caused by FIV are similar to human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes, and macrophages, with a similar replication cycle in infected cells. Thus, the infection of cats with FIV is also a useful tool for the study and development of novel drugs and vaccines against HIV. Anti-retroviral drugs studied extensively with regards to HIV infection have targeted different steps of the virus replication cycle: (1) disruption of the interaction with host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus and cell membranes; (3) blocking of the reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and integration of viral DNA into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite the great success of anti-retroviral therapy in slowing HIV progression in humans, a similar therapy has not been thoroughly investigated for FIV infection in cats, mostly because of the little structural information available for FIV proteins. The FIV capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. During this step, the CA protein oligomerizes to form a protective coat that surrounds the viral genome. In this work, we perform a large-scale screening of four hundred molecules from our in-house library using an in vitro assembly assay of p24, combined with microscale thermophoresis, to estimate binding affinity. This screening led to the discovery of around four novel hits that inhibited capsid assembly in vitro. These may provide new antiviral drugs against FIV.

Ebola Entry Inhibitors Discovered from Maesa perlarius

“…The diffusion behavior of the protein is altered later, when it is complexed with an increased number of unlabeled ligand molecules. The binding affinity ( K d ) of the ligand can be determined by obtaining the titration curves [ 31 ]. By definition, the dissociation constant ( K d ) refers to the concentration of ligand at which half of the ligand binding sites on the protein are occupied by the ligand molecules [ 32 ].…”

Preclinical Studies in Anti-Trypanosomatidae Drug Development

“…Even so, both structures are still considered Pan-Assay Interference Compounds (PAINS) because they also have groupings that can function as Michael acceptors with these able to nonspecific toxicity. However, despite extensive efforts, we were unable to identify what these nonspecific activities are for the compounds used here [ 14 , 27 , 28 , 29 ].…”

Review and Perspectives on the Structure–Function Relationships of the Gag Subunits of Feline Immunodeficiency Virus

“…Interestingly, GS-6207 binds at the CA/CA interface within HIV-1 CA hexamers and has been optimized from lead molecules using the structural data available on these hexamers [14,52,53]. For FIV, assembly inhibitors have recently been identified that bind the same region of CA, which seems to be similarly able to interact with feline nucleoporins [42,54] and thus represent an interesting therapeutic target. Obtaining structural data on FIV CA oligomers will therefore be of prime importance for the optimization of these compounds towards efficient anti-FIV molecules.…”