Over the past 35 years, the scientific community has achieved tremendous strides towards uncovering the mechanistic basis for myriad diseases. An early example of such success is the discovery by Peter Howley’s laboratory at the National Cancer Institute in the 1990s, of how the human papilloma virus (HPV) oncoprotein E6 usurps the host ubiquitin E3 ligase E6AP (also known as UBE3A) to induce degradation of the tumour suppressor p53 (Scheffner et al., 1993). This landmark study revealed the enzymatic activities required for HPV-driven cervical cancer and paved the way for the development of proteolysis-targeting chimeras (PROTACs) as a therapeutic strategy (Tsai et al., 2024). In parallel, the laboratories of Doug Lowy and John Schiller discovered that the HPV capsid protein L1 could be used to develop a vaccine to prevent HPV-driven cancers (Kirnbauer et al., 1992).

The discovery of viral-induced degradation of a host protein by hijacking the ubiquitination machinery inspired new therapeutic strategies whereby small molecules are used to direct the ubiquitination machinery to disease-associated proteins to induce their degradation. Following the discovery of E6-driven degradation of p53, a patent application for the PROTAC approach was submitted in 1999, and molecular targeting by PROTACs now fuels a growing sector of biomedical technology.