Protamine sulfate may prevent infections by pathogens that require heparan sulfate proteoglycan interactions, including high- and low-risk Human Papillomaviruses and Chlamydia trachomatis..

Abstract

e13065 Background: Human papillomaviruses (HPVs) are the most common pathogens of the reproductive tract with 80% of the population acquiring an infection at least once in their lifetime. Globally, high-risk (oncogenic) HPVs cause 630,000 new cancer cases per year and are responsible for 99% of cervical cancers. Regardless of available screening and preventive measures, cervical cancer is the fourth most common malignancy in women worldwide causing more than 445,000 new cases and 270,000 deaths annually. Like many pathogens of the reproductive tract, initiation of HPV infections require attachment to negatively-charged heparan sulfate proteoglycans (HSPG) present in the extracellular matrix and plasma membrane of host cells. To better define the role of HSPGs in HPV infections, we used protamine sulfate (PrS), a polycationic peptide that is FDA approved to neutralize heparin. Structural similarities between HSPGs and heparin allow PrS to bind HSPGs preventing HPV-HSPG interactions and infection. In order to further evaluate proof of concept for PrS we expanded our investigation to Chlamydia trachomatis, another genital tract pathogen whose mechanism of infection has been reported to rely on HSPGs. Methods: High and low risk HPV viruses were used in prophylactic and post exposure cell-based assays and a preclinical prophylactic mouse vaginal challenge model to evaluate the effects of PrS on infection. Chlamydia trachomatis serovar L2 was also used in prophylactic cell-based assays to evaluate the effects of PrS on infection. Results: A single dose prophylactic application of PrS reduced infection by high- and low-risk HPV genotypes by up to 95% in vitro (p-value < 0.001) in a dose response manner and 60% in vivo (p-value 0.05). In addition, post-HPV exposure PrS treatment significantly decreased infection. PrS showed the greatest effectiveness in the first two hours after HPV exposure. In line with our data on HPV, Chlamydia trachomatis infection showed a statistically significant decrease in cells pretreated with PrS (p-value 0.05). Conclusions: Inhibition of attachment by PrS presents a unique opportunity to provide a new cheap prophylactic modality for HPV infection, which would reduce cervical cancer global burden.