Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator

Abstract

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3–3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.

Capsid Assembly Modulators as Antiviral Agents against HBV: Molecular Mechanisms and Clinical Perspectives

“…This CAM molecule induces the formation of tight, normal nucleocapsid structures [ 76 ]. In vitro (HepAD38 cells and primary human hepatocytes (PHH)) as well as in vivo (mice models for HBV infection) studies demonstrated that GLP26 exhibits potent antiviral activity against HBV (EC 50 in the low nanomolar range) [ 76 , 77 ]. Moreover, GLP-26 alters cccDNA levels in cell culture models whereas a decrease in both HBeAg and HBsAg levels was observed both in vitro and in vivo.…”

Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma

“…Deployment of capsid inhibitors is also expected to slow down the emergence of virus mutants and permit the development of host immune responses that may clear virus replication completely, especially if combined with other modalities. Recent work has shown that such inhibitors are active in vivo with low toxicity and that some act synergistically with nucleoside analogs in a preclinical animal model [ 18 ]. Capsid inhibitors have also shown a modest decrease in the levels of HBV DNA in chronically infected patients [ 14 ].…”

Heterogeneous nuclear ribonucleoprotein A2B1, a novel drug target for hepatitis B virus infection

“…Therefore, new mechanisms inducing and regulating of type IFNs responses has attracted considerable attention [18][19][20] . Recently, hnRNPA2B1 has been viewed as an attracting regulatory protein of IFNs responses for viral infection 12,16 . hnRNPA2/B1, an RNA-binding protein as a member of the hnRNPs family, which plays an important roles in RNA biology and various disease 10,21 .…”

“…Herein, we assess the function of PAC5 on other viruses, such as pseudotyped SARS-CoV-2 and VSV-G infections. At present, pseudovirus (PsV) has become an ideal tool to analyze cell entry of SARS-CoV-2 without safety concerns and possess the morphological characteristics of replication-competent SARS-CoV-2, with the S protein on the envelope membrane 16 . Here, we first utilized SARS-CoV-2 PsV to perform a series of transduction assays.…”