Novel antivirals inhibit early steps in HPV infection

Abstract

The future incidence of cervical cancer is forecast to decline because of the remarkably effective prophylactic vaccines against human papillomaviruses. However, lack of access to these expensive vaccines in the developing countries where cervical cancer is most frequent, and the restricted genotypes these vaccines protect against, will limit their impact. Clearly, there is still a need for identifying other modalities for preventing HPV infections. Ready access to effective, inexpensive antivirals represents one potentially valuable approach to the prevention of genital HPV infections. We developed a well-validated high throughput screening (HTS) assay for identifying compounds that inhibit HPV infection and applied this assay to identify lead compounds that act by inhibiting an early step in infection. We screened over 40,000 small molecules that were available at the University of Wisconsin Small Molecule Screening Facility (UW-SMSF). The top 22 compounds were chosen for further analyses based upon the pharmacological property, scaffold diversity, strength of the inhibitory activity and lack of nonspecific cytotoxicity. Of these compounds, #13 and #14 had the most acceptable properties of low to submicromolar IC50’s and low cytotoxicity. Optimal antiviral activities were elicited by exposure of cells to the #13 and #14 during the initial 12 hours following infection. Twenty-nine #13-like and twelve #14-like analogs were identified in silico and tested for their antiviral activities corresponded to the altered structures comparing to #13 and #14, informing on the pharmacophore structure of each compound. Studies indicate that both compounds inhibit infection post entry.

Inhibition by Cellular Vacuolar ATPase Impairs Human Papillomavirus Uncoating and Infection

“…When administered postattachment, this molecule directs virions into a noninfectious internalization pathway (12). A recent screen of a small-compound library has identified new antiviral molecules that inhibit a notyet-defined postentry step of HPV infection (42). In the same line, lately a genome-wide siRNA screen has identified the retromer as a cellular factor required for HPV infection and shown that Retro-2, a small molecule inhibitor of retrograde transport, inhibits HPV16 infection (43).…”

Human Papillomavirus Biology, Pathogenesis, and Potential for Drug Discovery: A Literature Review for HIV Nurse Clinical Scientists

“…Articles focusing on the following were excluded: condylomata acuminate, abnormal cytology, vaccine titers, genotyping, HPV biology only in females, HPV head and neck cancers, basic viral infection, proctology, and herpes simplex virus. Table 1 Burk et al, 2009;Da Costa et al, 2002;Day & Schelhaas, 2014;Doorbar et al, 2006;Duncan et al, 2015;Guiguet et al, 2009;Hessol et al, 2009;Joyce et al, 1999;Kajitani et al, 2012;Machalek et al, 2012;Matthews et al, 2003;Middleton et al, 2003;Morshed et al, 2014;Munger et al, 2004;Pokomandy et al, 2011;Pyeon et al, 2009;Roden et al, 2001;Schiller et al, 2010;Stanley et al, 2012;Strickler et al, 2005;Uronis & Bendell, 2007 Use of HTS for drug discovery Basu et al, 2011;Buck et al, 2006;Huang et al, 2012;Kumar et al, 2011;Mahida et al, 2013;Marin et al, 2015;Thompson et al, 2010 Note. HPV = human papilloma virus; HTS = high-throughput screening techniques.…”

“…However, there are several limitations to the vaccine. It is expensive, recommended to be administered between the ages of 9 and 26 years of age, and prior to sexual debut (Huang et al, 2012;Palefsky et al, 2011). The age and sexual debut restrictions on the administration of HPV vaccines create a gap in the continuum of care for anyone ages 26 years and older and anyone who has achieved sexual debut (Palefsky et al, 2011).…”

“…HTS has the potential to be used to identify compounds able to modulate HPV infection (Buck et. al., 2006;Huang et al, 2012). Identification of these compounds is the first step in the development of new drugs for treatment and prevention.…”

“…The automated process uses liquid handling and robotic arms to inject small volumes of drugs or molecules into 384-well plates in several hours. Through this process, one can rapidly identify active compounds that modulate a particular HPV biomolecular pathway (Huang et al, 2012). The alternative method involves manual pipetting of each compound into an individual well on a 384-well plate.…”