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Human Papillomavirus (HPV) is the leading cause of cervical cancer, with only a portion of HPV types prevented with vaccines and no treatments for the viral infection itself. Inhibiting the formation of the viral capsid is one way to target the viral infection. This can be done by inhibiting the assembly of the L1 monomer into a pentamer, which forms the viral capsid. Four calix[4]arene compounds functionalised with D-and L-aspartic and glutamic acid were synthesised and tested for L1 pentamer formation inhibition, in addition to an iminodiacetic functionalised calix [4]arene. The amino acid functionalised calix[4]arene derivatives showed millimolar inhibition (IC50 = 0.72 to 2.67 mM) of L1 pentamer formation, with a small difference between the inhibitory concentrations of the stereoisomers. The iminodiacetic acid calix[4]arene derivative showed no inhibitory properties, despite sharing structural similarities with the four other calix[4]arenes, suggesting the flexibility of the amino acid side chain and/or the hydrogen of the secondary amide were important for the compounds to bind to the L1 protein. Confirmation of binding the negatively charged compounds to the positive residues of the L1 protein was achieved with a trypsin digestion. This study will be helpful to develop cost-effective inhibitor to prevent HPV assembly.

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Human papillomavirus (HPV) infections are the cause of warts, lesions and cancer, with different types of HPV causing different symptoms. HPV infections are the primary cause of cervical cancer. There are over 220 different types of HPV, and only nine of these can currently be vaccinated. There is a need to treat these viral infections without just treating the symptoms of the infection, as is currently the main method. There is a wide range of small molecules that have been used to inhibit various stages of the HPV infectious cycle. This review examined 132 small molecules from 121 studies that specifically target aspects of HPV infections. HPV DNA encodes for six early genes (E1 to E7, skipping E3) and two late genes (L1 and L2). According to the results, these targets for small molecule inhibitors fall into three categories: those targeting E1 and E2, targeting E6 and E7 and, finally, targeting L1 and L2. Inhibitors of E6 and E7 are the most widely studied targets, with the majority of HPV inhibition in this area. While compounds targeting both E1/E2 and E6/E7 have made it to clinical trials, there has been no significant advancement on the topic.