A Phase 1a, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Determine the Safety and Pharmacokinetics of AV-1 in Healthy Male and Female Adult Subjects

AV-1 is a human monoclonal antibody (mAb) being investigated as a potential therapy for dengue, a mosquito-borne viral disease with extensive global public health impact. Globally, over 2 billion people are thought to be at risk of infection from the dengue virus and there are an estimated 390 million infections each year. Current treatment options for dengue are limited to supportive care, so a safe and effective treatment would provide substantial public health benefits. AV-1 has not previously been tested in humans. This study aims to determine the safety of AV-1 in healthy adult volunteers, when administered as a single IV infusion. The results of the study are based on the clinical study report and statistical analysis plan.

Start Date04 Feb 2020

Sponsor / Collaborator

AbViro LLCStartup

[+1]

100 Clinical Results associated with DENV envelope

100 Translational Medicine associated with DENV envelope

0 Patents (Medical) associated with DENV envelope

Literatures (Medical) associated with DENV envelope

28 Aug 2020·Journal of Natural ProductsQ2 · BIOLOGY

Carneic Acids from an Endophytic Phomopsis sp. as Dengue Virus Polymerase Inhibitors

Q2 · BIOLOGY

Article

Author: Litaudon, Marc ; Guillemot, Jean-Claude ; Eparvier, Véronique ; Peyrat, Laure-Anne ; Stien, Didier ; Eydoux, Cécilia

Thirteen carneic acids were isolated from the fungal endophyte Phomopsis sp. SNB-LAP1-7-32. Their structures were identified by mass spectrometry and extensive one- and two-dimensional NMR spectroscopy and through comparison with data reported in the literature. Compounds 1-13 were investigated for their antipolymerase activities against DENV polymerase and Zika NS5. Five of them exhibited significant inhibition of dengue polymerase with IC₅₀ values in the 10 to 20 μM range without cytotoxicity. None inhibited Zika virus NS5 protein.

01 Nov 2014·Antiviral ResearchQ2 · MEDICINE

Crystal structure of dengue virus methyltransferase without S-adenosyl-L-methionine

Q2 · MEDICINE

Article

Author: Dong, Hongping ; Shi, Pei-Yong ; Li, Shi-Hua ; Noble, Christian G ; Chew, Sock Hui

Flavivirus methyltransferase is a genetically-validated antiviral target. Crystal structures of almost all available flavivirus methyltransferases contain S-adenosyl-L-methionine (SAM), the methyl donor molecule that co-purifies with the enzymes. This raises a possibility that SAM is an integral structural component required for the folding of dengue virus (DENV) methyltransferase. Here we exclude this possibility by solving the crystal structure of DENV methyltransferase without SAM. The SAM ligand was removed from the enzyme through a urea-mediated denaturation-and-renaturation protocol. The crystal structure of the SAM-depleted enzyme exhibits a vacant SAM-binding pocket, with a conformation identical to that of the SAM-enzyme co-crystal structure. Functionally, equivalent enzymatic activities (N-7 methylation, 2'-O methylation, and GMP-enzyme complex formation) were detected for the SAM-depleted and SAM-containing recombinant proteins. These results clearly indicate that the SAM molecule is not an essential component for the correct folding of DENV methyltransferase. Furthermore, the results imply a potential antiviral approach to search for inhibitors that can bind to the SAM-binding pocket and compete against SAM binding. To demonstrate this potential, we have soaked crystals of DENV methyltransferase without a bound SAM with the natural product Sinefungin and show that preformed crystals are capable of binding ligands in this pocket.

01 Dec 2012·Protein Engineering Design and SelectionQ4 · BIOLOGY

Transplantation of a hydrogen bonding network from West Nile virus protease onto Dengue-2 protease improves catalytic efficiency and sheds light on substrate specificity

Q4 · BIOLOGY

Article

Author: Chandrakala Basavannacharya ; M.S. Madhusudhan ; Danny N.P. Doan ; Subhash G. Vasudevan ; Kun Quan Li

The two-component serine protease of flaviviruses such as Dengue virus (DENV) and West Nile virus (WNV) are attractive targets for inhibitor/therapeutic design. Peptide aldehyde inhibitors that bind to the covalently tethered two-component WNV protease (WNVpro) with 50% inhibitory concentration (IC(50)) at sub-micromolar concentrations, bind the equivalent DENV-2 protease (DEN2pro) with IC(50) of micromolar concentrations at best. Conversely, the protease inhibitor aprotinin binds DEN2pro ∼1000-fold more tightly than WNVpro. To investigate the residues that are crucial for binding specificity differences, a binding-site network of hydrogen bonds was transplanted from WNVpro onto DEN2pro. The transplantations were a combination of single, double and triple mutations involving S79D, S83N and S85Q. The mutant DENV proteases, except those involving S85Q, proved to be more efficient enzymes, as measured by their kinetic parameters. The binding affinities of the mutants to peptide inhibitors however showed only marginal improvement. Protein structure modeling suggests that the negatively charged residue cluster, Glu89-Glu92, of the NS2B cofactor may play an important role in determining substrate/inhibitor-binding specificity. These same residues may also explain why aprotinin binds more tightly to DEN2pro than WNVpro. Our results suggest that structure-based inhibitor design experiments need to explicitly consider/include this C-terminal region whose negative charge is conserved across the four DENV serotypes and also among the flavivirus family of proteases.

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