Novel Peptides Bind Elusive Therapeutic Target Critical to HIV Lifecycle
Available for Licensing
US Utility Patent: US 10,538,556
US Utility Patent Pending: US 2020/0115418 A1
David W Crawford
At A Glance
Researchers at Colorado State University have developed cyclic peptides with high affinity binding to the HIV-1 Trans-activation response (TAR) element RNA – a validated drug target, that is highly resistant to mutation. Structural analysis and experimentation revealed these cyclic proteins 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. Drugs from different classes are taken concurrently, called antiretroviral therapy (ART), because 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. Yet, drug resistance remains an ongoing issue, due to high rate of mutation by the HIV virus.
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. New targets, resistant to mutation (such as the HIV-1 TAR element RNA), are needed to improve long term therapeutic outcomes.
- 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
- Cyclic peptides are highly selective to HIV-1 TAR, and bind with high affinity
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: April 2020