Background

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).

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.

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.

Technology Overview

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.

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

Publication

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.

Last updated on October 7, 2019.