The Discovery and Preclinical Profile of ALG-000184, a Prodrug of the Potent Hepatitis B Virus Capsid Assembly Modulator ALG-001075.

Chronic hepatitis B (CHB) represents a significant unmet medical need with few options beyond lifelong treatment with nucleoside analogues, which rarely leads to a functional cure. Novel agents that reduce levels of HBV DNA, RNA and other viral antigens could lead to better treatment outcomes. The capsid assembly modulator (CAM) class of compounds represents an important modality for chronic suppression and to improve functional cure rates, either alone or in combination.

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor.

Biochemical simulation of mutation synthesis and repair during SARS-CoV-2 RNA polymerization.

We biochemically simulated the mutation synthesis process of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex (nsp7/nsp8/nsp12) involving two sequential mechanistic steps that occur during genomic replication: misinsertion (incorporation of incorrect nucleotides) and mismatch extension. Then, we also simulated mismatch repair process catalyzed by the viral nsp10/nsp14 ExoN complex. In these mechanistic simulations, while SARS-CoV-2 RdRp displays efficient mutation synthesis capability, the viral ExoN complex was able to effectively repair the mismatch primers generated during the mutation synthesis.