Date on Master's Thesis/Doctoral Dissertation

12-2021

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Palmer, E. Kenneth

Committee Co-Chair (if applicable)

Mitchell, Thomas C.

Committee Member

Mitchell, Thomas C.

Committee Member

Alard, Pascale

Committee Member

Sokoloski, Kevin

Committee Member

Joongho, Joh

Committee Member

Matoba, Nobuyuki

Author's Keywords

Lectins; Griffithsin: Q-Griffithsin; antifungals; antivirals; COVID-19

Abstract

Griffithsin (GRFT) is a carbohydrate binding agent (lectin) that was originally identified in the red alga Griffithsia sp. Q-Griffithsin (Q-GRFT) is an oxidation stable analog of GRFT. GRFT has demonstrated inhibitory activity against HIV-1, Coronaviruses, Hepatitis C, influenza and Ebola viruses. The broad-spectrum activity suggests the potential utility of this lectin in a wide range of viral infections. However, the lectin’s activity in mucosal infections has not been extensively studied. Using in vitro, ex vivo and in vivo assays, we have demonstrated that Q-GRFT maintains the ability to bind glycosylated ligands following incubation in murine, macaque and human rectal fluids. Additionally, we demonstrated the first reported in vitro findings of antifungal activity by Q-GRFT. Furthermore, in murine prophylaxis and therapeutic infection models, Q-GRFT was efficacious against vaginal candidiasis. In response to the ongoing COVID-19 pandemic, we have demonstrated that in engineered human cornea and airway epithelia, repeated topical application resulted in Q-GRFT accumulation in mucosal tissues. In addition, in a human cadaver study, intranasal administration resulted in adequate drug dispersion on the nasal, nasopharyngeal and oropharyngeal cavities, with the drug detected in fluids collected from these anatomic sites. These findings support the development of a protocol for a Phase 1a first-in-human intranasal Q-GRFT administration to evaluate safety, tolerability, and pharmacokinetics of the drug product for pre-exposure prophylaxis against coronaviruses. Altogether, these data demonstrated Q-GRFT’s stability in the mucosal environment and support its incorporation in multipurpose STI prevention modalities given the novel antifungal activity. Epithelial accumulation and ability to detect Q-GRFT in nasal specimens supports the feasibility of successfully performing the Phase 1a study and future drug development as a prophylaxis against coronaviruses.

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