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Background & Aims: Bulevirtide (BLV) is a first-in-class entry inhibitor and the only approved treatment for patients chronically infected with HDV in Europe. We aimed to investigate the efficacy of BLV treatment in paired liver biopsies obtained at baseline and after 24 or 48 weeks of treatment., Methods: We performed a combined analysis of 126 paired liver biopsies derived from three clinical trials. In the phase II clinical trial MYR202, patients with chronic hepatitis D were randomised to receive 24 weeks of BLV at 2 mg, 5 mg or 10 mg/day. Patients in MYR203 (phase II) and MYR301 (phase III) received 48 weeks of BLV at 2 mg or 10 mg/day. Tenofovir disoproxil fumarate monotherapy or delayed treatment served as comparators. Virological parameters and infection-related host genes were assessed by qPCR and immunohistochemistry., Results: At week 24, median intrahepatic HDV RNA decline from baseline was 0.9Log 10 with 2 mg (n = 7), 1.1Log 10 with 5 mg (n = 5) and 1.4 Log 10 with 10 mg (n = 7) of BLV. At week 48, median reductions were 2.2Log 10 with 2 mg (n = 27) and 2.7Log 10 with 10 mg (n = 37) of BLV, while HDV RNA levels did not change in the comparator arms. Notably, a drastic decline in the number of hepatitis delta antigen-positive hepatocytes and a concomitant decrease in transcriptional levels of inflammatory chemokines and interferon-stimulated genes was determined in all BLV-treatment arms. Despite the abundance of HBsAg-positive hepatocytes, replication and covalently closed circular DNA levels of the helper virus HBV were low and remained unaffected by BLV treatment., Conclusion: Blocking viral entry diminishes signs of liver inflammation and promotes a strong reduction of HDV infection within the liver, thus suggesting that some patients may achieve HDV cure with long-term treatment., Impact and Implications: Chronic infection with HDV causes the most severe form of viral hepatitis, affecting approximately 12 million people worldwide. The entry inhibitor bulevirtide (BLV) is the only recently approved anti-HDV drug, which has proven efficacious and safe in clinical trials and real-word data. Here, we investigated paired liver biopsies at baseline and after 24 or 48 weeks of treatment from three clinical trials to understand the effect of the drug on viral and host parameters in the liver, the site of viral replication. We found that BLV treatment strongly reduces the number of HDV-infected cells and signs of liver inflammation. This data implies that blocking viral entry ameliorates liver inflammation and that prolonged treatment regimens might lead to HDV cure in some patients. This concept will guide the further development of therapeutic strategies and combination treatments for patients with CHD., Clinical Trial Numbers: NCT03546621, NCT02888106, NCT03852719., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A plenty of natural products and synthetic derivatives containing quinoline moiety have been reported to possess various pharmacological activities. Quinolines such as 2-styrylquinolines and 8-hydroxyquinolines are extensively studied for their anti-HIV-1 activity and found to act mainly through HIV-1 integrase enzyme inhibition. In continuation of our efforts to search for newer anti-HIV-1 molecules, thirty-one quinoline derivatives with different linkers to ancillary phenyl ring were synthesized and evaluated for in vitro anti-HIV-1 activity using TZM-bl assays. Compound 31 showed higher activity in TZM-bl cell line against HIV-1 VB59 and HIV-1 UG070 cell associated virus (IC 50 3.35 ± 0.87 and 2.57 ± 0.71 μM) as compared to other derivatives. Compound 31 was further tested against cell free virus HIV-1 VB59 and HIV-1 UG070 (IC 50 1.27 ± 0.31 and 2.88 ± 1.79 μM, TI 42.20 and 18.61, respectively). This lead molecule also showed good activity in viral entry inhibition assay and cell fusion assay defining its mode of action. The activity of compound 31 was confirmed by testing against HIV-1 VB51 in activated peripheral blood mononuclear cells (PBMCs). Binding interactions of 31 were compared with known entry inhibitors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aptamers, which are artificial nucleic acid ligands akin to antibodies in function, represent a new class of molecules that can prevent HIV infection. In this study, we isolated RNA aptamers against whole HV-1CAP45 enveloped pseudotyped virus, with a view to target surface molecules that facilitate infection, such as the envelope protein, in their native form. HIV-1CAP45 belongs to subtype C viruses endemic in Sub-Saharan Africa and responsible for the majority of the global HIV-1 infections. After nine rounds of the systematic evolution of ligands by exponential enrichment (SELEX) method, we isolated twenty-three aptamer clones that inhibited infection of target cells by HIV-1CAP45 with 50% inhibitory concentration (IC50) values of 0.1-50 nM. Four of these aptamers called CSIR1.1, CSIR1.4, CSIR1.5 and CSIR1.6 bound to gp120 with affinity constant (KD) values between 16.9 and 195 nM and one aptamer called CSIR1.2 bound gp41. Interestingly, one aptamer called CSIR1.3 that did not bind gp120 or gp41 also inhibited infection of the target cells by HIV-1CAP45 with IC50 of less than 5 nM. Taken together, these data show that the aptamers inhibit infection of HIV-1CAP45 by binding to gp120 or gp41, or other viral surface molecules necessary for infection. The results argue in favour of using these aptamers as analytical tools to further probe HIV-1 entry, and their future development as HIV-1 entry inhibitors., (Copyright © 2014 Elsevier Inc. All rights reserved.)