# Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections

> **NIH NIH R43** · KOVINA THERAPEUTICS INC. · 2022 · $298,527

## Abstract

Human papillomaviruses (HPV) cause exceedingly common infections of cutaneous and
mucosal epithelia. Infection with specific “high risk” HPV genotypes can progress to pre-
malignant lesions called dysplasias, which over a period of years, can eventuate in invasive and
metastatic epithelial malignancies. Our therapeutic goal is to treat early stage infections of the
cervix, genitalia, and anus that afflict millions of women and men before these progress to invasive
cancers.
 Kovina Therapeutics strategy is to eliminate HPV infection by selectively targeting the E6
protein and preventing interactions with its cellular binding partners. E6 is necessary for viral
genome replication and maintenance and is always expressed in HPV-associated dysplasia and
malignancies. We performed in silico screening of chemical libraries for small molecules that
would resemble the interface of E6 with several of its cellular partners. Our assays focused on the
protein-protein interaction of E6 with the ubiquitin ligase E6AP, which mediates ubiquitination and
proteasome mediated destruction of the tumor suppressor protein p53. Using this model, we
designed and synthesized compounds that 1) bind to HPV-16 E6 and 2) are armed with a ‘warhead’
to make a covalent bond with a specific cysteine in HPV-16 E6 binding pocket for E6AP. The
approach to identify molecules equipped with reactive warheads that mediate covalent and
irreversible binding to cysteine is exemplified in several new clinically available drugs that target
proteins previously considered undruggable. We discovered several compounds covalently bound
to E6 via this cysteine residue, block E6 interaction with E6AP, restore P53 function, and induce
death of HPV-16 expressing cells. Multiple biochemical analyses including X-ray crystallography
prove these inhibitors occupy the targeted E6 pocket and form a single adduct with this cysteine.
Iterative optimization guided by the co-crystal data enabled design and synthesis of >80 novel
compounds and has resulted chemotypes with increased activity. This one-year Phase I SBIR
proposal plans to screen our existing E6 inhibitor collection to determine their biological activities
in cell-based assays and pharmacokinetic properties that would meet FDA guidelines for a topical
agent. We will initiate drug development studies including formulation for topical application and
early stage pharmacokinetic and toxicology characterization. The success of Phase I study will
validate this antiviral strategy and position us to proceed to apply for a Phase II SBIR to perform
IND-enabling studies.

## Key facts

- **NIH application ID:** 10390563
- **Project number:** 1R43AI167573-01
- **Recipient organization:** KOVINA THERAPEUTICS INC.
- **Principal Investigator:** ELLIOT J. ANDROPHY
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $298,527
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390563

## Citation

> US National Institutes of Health, RePORTER application 10390563, Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections (1R43AI167573-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10390563. Licensed CC0.

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