Description:
Novel Peptides Bind Elusive Therapeutic Target Critical to HIV Lifecycle
Inventors - Brian McNaughton and David Crawford
At a Glance
McNaughton and Crawford have developed cyclic peptides with high affinity binding to the HIV-1 Trans-activation response (TAR) element RNA - a validated drug target comprising conserved, bulged stem-loop structures that are critical in facilitating pro-viral transcription and blocking apoptosis in an infected host cell.
Existing FDA-approved drugs target many facets of the viral life cycle, however, modulations of new targets, resistant to mutation (such as the HIV-1 TAR element RNA), are needed to improve long term therapeutic outcomes.
HIV/AIDS afflicts nearly 37 million people worldwide, with a high rate of mutation – at present there is no cure or vaccine.
Background
Technology: To identify cyclic peptides, the inventors undertook a fundamentally different “semi-design” strategy that uses laboratory evolution to alter putative RNA-binding amino acids within a known protein. Using saturation mutagenesis, a library of small proteins was developed, allowing the inventors to screen and identify desired proteins capable of TAR-binding. From those selected, structural analysis and experimentation revealed several variants that exhibited extraordinarily tight TAR affinity and impaired TAR binding to the Tat peptide (attenuating Tat dependent transcription).
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. This type of therapy is called antiretroviral therapy (ART). Each class of drug blocks the virus in a different way. 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.
Competitive Landscape: The HIV antiretroviral market is highly competitive, with the availability of numerous effective therapies and several players losing patent protection in the coming years. Because HIV patients must remain on treatment indefinitely, novel therapies that can penetrate viral reservoirs should offer greatly improved outcomes and would be an important addition to this crowded landscape. Due to the high rate of mutation of the HIV virus, drug resistance remains an ongoing issue; thus, targeted antivirals will always be in demand.
Approach: New antivirals must be developed to combat drug resistance, while addressing the needs of an aging population requiring decades of therapy compliance. Current FDA-approved drugs target many facets of the viral life cycle, however, there is a need for new targets that are resistant to mutation to improve long-term therapeutic outcomes. Research has shown, the HIV-1 TAR element RNA is a validated drug target comprising a conserved, bulge stem-loop that is highly resistant to mutation. The TAR plays a critical role in facilitating pro-viral transcription and blocking apoptosis of the infected host cell – imperative to the HIV life cycle. Although it is well known that TAR is a target worth pursuing, it has been refractory to the discovery of small molecules or peptides with sufficient affinity and selectivity warranting pharmaceutical development.
Summary:
The Anti-HIV Cyclic Proteins developed by McNaughton and Crawford, sufficiently bind TAR (a well-known drug target, that is not only highly resistant to mutation, but a sought-after market. In doing so, these short conformationally-constrained peptides suppress Tat-mediated transcription in a dose-dependent manner.
Benefits
Therapeutic target (HIV-1 TAR) has been validated for therapeutic use
HIV-1 TAR is highly conserved and highly resistant to mutation
HIV-1 TAR has been refractory to the discovery of peptides or small molecules by competitors, as affinity and selectivity is a crucial parameter for drug development
Thusly, cyclic peptides are novel in the market
Cyclic peptides are highly selective to HIV-1 TAR, and bind with high affinity
Seeking
Licensing Partner
Additional funding to further prospective research
IP Status
US Utility patent pending
PCT patent pending
Relevant Publications
Belashov, Ivan A, et al. “Structure of HIV TAR in Complex with a Lab-Evolved RRM Provides Insight into Duplex RNA Recognition and Synthesis of a Constrained Peptide That Impairs Transcription.” Nucleic Acids Research, vol. 46, no. 13, 2018, pp. 6401–6415., doi:10.1093/nar/gky529.
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.
