Pharmaceuticals & Vitamin D : Antivirals


Enhanced HIV Treatments: Boronic Acid Group Improves Drug Potency

UW–Madison researchers have developed new, more potent protease inhibitors, particularly aspartyl protease inhibitors such as those that inhibit HIV protease.

To make the new inhibitors, certain aryl groups in existing inhibitors are replaced with aryl boronic acid groups, leading to significantly enhanced activity. The boronic acid group may be protected with a protecting group that can be removed in vivo to provide an HIV protease inhibitor prodrug.

Inhibitors of Ebola and Other Filoviruses

UW-Madison researchers have developed a method of using the modified, biologically contained form of Ebola to identify potential new treatments for Ebola infection. They discovered that the existing drug benztropine mesylate, which is approved for the treatment of Parkinson’s disease and other dystonia disorders, interferes with Ebola infection and virus uptake.

The researchers also identified several other agents that inhibit Ebola infection. The agents include triphenylethylene, steroids, anticholinergics, dopamine antagonists and inhibitors of calcium-independent phospholipase A2, magnesium-dependent phosphatidate phosphohydrolase and PGE2 synthase, among others. They can be administered to a human or other mammal to prevent or treat viral infections.

Better Living Through Peptides; Improved Approach to HIV Therapy

UW–Madison researchers have developed a new method to fabricate combination alpha and beta peptides for the treatment of HIV and other disorders.

Because beta amino acids are non-natural, they are resistant to proteolysis. Substituting beta amino acids for some of the alpha amino acids in fusion inhibitors increases resistance to proteolysis with little effect on efficacy. The resulting α/β-peptide combination lasts longer and is less likely to cause drug resistance, leading to improved outcomes for HIV patients. This technique is also applicable to other peptide-based therapeutics.

Small Molecule Therapeutics to Inhibit HPV Infection

UW–Madison researchers have developed new methods and compositions for inhibiting HPV infection. These inhibitors could complement and/or replace current vaccine treatment.

The researchers found that cell cycle progression through mitosis is critical for HPV infection. Host cells must pass through early prophase before transcription of HPV-encapsidated genes. Exposing a papillomavirus to an effective amount of a G1, S, G2 or early M phase cell cycle inhibitor or administering one of the inhibitors to a susceptible tissue or cell therefore provides a new approach to the prevention and treatment of HPV infection.

Novel Antiviral Peptides Against Influenza Virus

UW-Madison researchers now have developed truncated versions of the EB peptide that can be used to prevent or treat influenza viral infections. These shorter peptides exhibit antiviral activity against influenza viruses that is comparable to or better than that of EB. Like EB, they inhibit the attachment of influenza virus to host cells, preventing viral infection. However, some of these shorter peptides likely work through a different mechanism than EB. 

Antiviral Peptides and Methods for Inducing Cellular Resistance to Infection

UW–Madison researchers have developed peptides that are active against a broad spectrum of viruses. These peptides may be useful as prophylactic or therapeutic agents to treat multiple viral respiratory tract infections, eliminating the need for specific vaccines.

The peptides do not need to enter cells to inhibit viral infection. Instead, the peptides permanently inactivate virions in solution and can block viral infection at post-attachment steps such as during cell entry. Additionally, when cells in culture are treated with the peptides, the cells become resistant to infection for up to several hours. The cellular resistance is reinducible, and the treated cells become resistant within five minutes of exposure to the peptides.

Animal studies have confirmed that the peptides are active against influenza virus and protect from death even when administered 24 hours post-infection. Preliminary toxicity data show the peptides are not toxic to cells in culture at concentrations up to 150-200 micromolar. They are also not toxic in vivo at doses one thousand times higher than the IC50 values.

Reverse Genetics Approach for Generating Ebola Virus and Other Filoviruses from Cloned DNA

Kawaoka and his colleagues have now developed a reverse genetics approach for generating Ebola virus entirely from cloned cDNA. They prepared the full Ebola genome through reverse transcription of viral RNA, followed by PCR amplification and cloning of Ebola cDNA. They then successfully produced infectious viral particles by transfecting host cells with plasmids carrying Ebola cDNA, along with plasmids expressing Ebola proteins L, NP, VP30 and VP35 (needed for transcription and replication of negative strand RNA viruses), and one encoding the T7 RNA polymerase.

The researchers also used the system to make mutant virus particles containing an altered furin recognition motif. Furin cleaves Ebola virus glycoprotein at a highly conserved sequence motif, an event hypothesized to be critical to viral pathogenicity. However, viral particles carrying the altered motif still showed pathogenicity and ability to replicate in culture. This result illustrates the system’s utility for hastening our understanding of the Ebola virus life cycle and the development of anti-viral agents.

Novel Analogs of Podophyllotoxin May Treat Cancer and Viral Infections

UW–Madison researchers have now synthesized a library of podophyllotoxin derivatives using the neoglycorandomization method. The new derivatives may be useful for treating cancer or as antivirals.

Novel Small Molecule SIRT6 Activators/Inhibitors

UW–Madison researchers have developed three novel compounds (CL-5D, SW-055, SW-062) that activate SIRT6 in biochemical assays. Two other compounds (CL-5D-Me and SW-055-Me) are methyl esters that are not expected to be active in biochemical assays but are expected to be more cell permeable and act as prodrugs, becoming active upon ester hydrolysis in cells.