Description:
Helix Grafted Proteins Inhibition of HIV-1 Infection
Inventors:
Brian R McNaughton
Alan J Kennan
Susanne N Walker
Rachel L Tennyson
Alex M Chapman
At a Glance
McNaughton et al. engineered helix-grafted scaffolds capable of inhibiting HIV infection in a live-virus assay, by disruption of gp41 (the crucial c-terminal sequence responsible for enabling fusion of the HIV-1 virus to the host cell and thusly, infection).
Existing FDA-approved HIV drug therapies, such as T20 (marketed as Fuzeon) have proven to be capable inhibitors of gp41. And although these therapies have validated efficacy and relevance, T20 is coupled with significant draw backs: (1) extraordinarily expensive, and (2) a half-life of only 4 hours in vivo.
HIV/AIDS afflicts nearly 37 million people worldwide, with a high rate of mutation – strongly suggested a need for more innovative therapies.
Background
Technology: The general concept of protein grafting is an established method for mimicking protein surfaces; however, the steps to generate a successful therapeutic have eluded most. The inventors were able to identify a scaffold protein with the ability to serve as a generic canvas to apply the groups “helix-grafting” technique. The scaffold protein itself, met numerous qualifications including: (1) bearing a helix with at least one solvent-exposed face; (2) stable enough to facilitate easy expression; and (3) tolerate varying the exposed helical residues and overall helix length. The fusion enabled the helix grafted protein to interact with a crucial protein-protein interaction, gp41, responsible for HIV infection into healthy CD4 T-cells.
Market: Global HIV Drug Market was valued at $20,448 million in 2015 and is expected to garner $26,458 million by 2022, registering a CAGR of 3.7% during the forecast period 2016-2022. The North America region accounted half of the share in the overall HIV drug market in 2015 and is expected to maintain this lead throughout the forecast period. The major factors that boost the HIV drug market growth include increase in prevalence of HIV and rise in treatment & diagnosis rate (especially in markets with well-established healthcare systems such as the North American region). Moreover, there is an increase in the government initiative to increase awareness among people about HIV cause, symptoms, available treatment options, and the crucial role of these treatments in the control of HIV virus growth. Thus, rise in awareness through such government initiatives are also expected to drive the HIV drugs market.
Technology Overview: Where do we fit in?
Current Treatment: There is no cure for HIV/AIDS, but there are many drugs available to control the virus using antiretroviral therapy (ART). ART is recommended for everyone infected – and most often in a combination of three drugs from any two classes to avoid creating drug-resistant strains of HIV. Each class of drug blocks the virus in a different way. The classes include:
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs)
Protease inhibitors (PIs)
Entry or fusion inhibitors
Integrase inhibitors
Competitive Landscape: The helix-grafted scaffold protein engineered by McNaughton et al fits into the entry or fusion inhibitors class. This class, unlike the others, is wide open in terms of competition. Only two main competitors exist in the market and make up 20% of the options for physician recommended therapy – these include (1) Fuzeon (Roche), and (2) Selzentry (ViiV Healthcare). As mentioned previously, although these drugs are proven effective inhibitors of HIV entry, they have other draw backs – not limited to price and half-life.
Approach: The group began with the premise that isolated helical fragments themselves were poor starting points for either discovery or application of new ligand sequences. The small lengths needed for protein-protein interface (PPI) interactions complicated not only production but also stability. Additionally, chemical synthesis on a therapeutically viable scale is a significant challenge, greatly adding to the cost. These shortcomings fueled the group’s search for alternative structures that could mimic native PPI ligands. Stably folded peptides with intrinsic helical domains with key residues for specific PPI was determined to be a likely solution to overcome the challenges presented by current drug discover techniques. The next step was to find the right scaffold to graft a potential helix to. Given the demonstrated efficacy of the therapeutically relevant drug Fuzeon (T20), McNaughton et al chose the gp41 c-terminal sequence as the initial target for helix grafting.
Summary: The helix-grafted scaffold proteins significantly lowered the incidence of HIV-1 infection in CD4 positive cells. In addition, the helix-grafted proteins: (1) expressed well as recombinant proteins with relative stability in human serum; (2) were able to sufficiently bind gp41 in vitro and complex biological environments; and (3) had extended half lives relative to their competitors.
Benefits
Therapeutic target (gp41) has been validated for therapeutic use
gp41 is essential to HIV infection – with only one other competitor binding to this specific complex
With only two competitors in the fusion/entry class, there is truly room to capture a larger percent of the market in comparison to the other classes
Helix-grafted scaffold proteins are human derived and fold naturally allowing them to bind with high affinity to the gp41 complex
The helix-grafted scaffold protein is a likely canvas for further drug discover in related fields
Relevant Publications:
Walker, Susanne N., et al. “GLUE That Sticks to HIV: A Helix-Grafted GLUE Protein That Selectively Binds the HIV gp41 N-Terminal Helical Region.” ChemBioChem, vol. 16, no. 2, 2014, pp. 219–222., doi:10.1002/cbic.201402531.
Tennyson, Rachel L., et al. “Helix-Grafted Pleckstrin Homology Domains Suppress HIV-1 Infection of CD4-Positive Cells.” ChemBioChem, vol. 17, no. 20, 2016, pp. 1945–1950., doi:10.1002/cbic.201600329.
References
“Strategic Analysis of Antiviral Drug Development for Viral Hepatitis and HIV/Aids.” Cds.frost.com, 26 Mar. 2013, https://cds.frost.com/p/36239/#!/nts/c?id=9837-00-57-00-00&hq=HIV.
“HIV Drug Market by Medication Class [Multi-Class Combination Drugs, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Fusion Inhibitors (FI), Entry Inhibitors, and HIV Integrase Stand Transfer Inhibitors] - Global Opportunity Analysis and Industry Forecast, 2014-2022.” Allied Market Research, Feb. 2017, www.alliedmarketresearch.com/hiv-drugs-market.
“HIV/AIDS.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 19 Jan. 2018, www.mayoclinic.org/diseases-conditions/hiv-aids/diagnosis-treatment/drc-20373531
"Enfuvirtide." Wikipedia, The Free Encyclopedia, 6 Jan 2019, 21:55 UTC, https://en.wikipedia.org/w/index.php?title=Enfuvirtide&oldid=877147474
“Maraviroc.” Wikipedia, The Free Encyclopedia, 19 November 2018, 00:56 UTC, https://en.wikipedia.org/w/index.php?title=Maraviroc&oldid=869501705
