Polyanionic
macromolecules including carboxylate-terminated polymers (polycarboxylates)
are capable of inhibiting sexually transmitted viruses such as human
immunodeficiency virus (HIV) and herpes simplex virus (HSV). Cellulose
acetate phthalate (CAP), a pharmaceutically acceptable pH-sensitive
polycarboxylate polymer, showed promising prophylactic activity against
HIV and HSV, but the instability of CAP in an aqueous environment
prevented its clinical development. Interestingly, several pharmaceutically
acceptable polycarboxylates have features similar to CAP with an aqueous
stability significantly higher than that of CAP. However, their activity
against sexually transmitted viruses remains unexplored. Here, we
evaluate the activity of various polycarboxylates such as polyvinyl
acetate phthalate (PVAP), various grades of hydroxypropyl methylcellulose
phthalate (HPMCP-50, HPMCP-55, and HPMCP-55S), and various grades
of methacrylic acid copolymers (Eudragit L100-55, Eudragit L100, Eudragit
S100, and Kollicoat MAE 100P) against HSV. We, for the first time,
demonstrate that PVAP, HPMCP-55S, and Eudragit S100 have activity
and selectivity against HSV-1 and HSV-2. Further, we report that polycarboxylates
can be easily transformed into nanoparticles (NPs) and in the nanoparticulate
form, they show similar or enhanced activity against HSV. Finally,
using PVAP NPs, as a model, we demonstrate using in vitro HSV therapy
studies that polycarboxylate NPs are capable of synergizing with antiviral
drugs such as acyclovir (ACV), tenofovir, and tenofovir disoproxil
fumarate. Thus, pharmaceutically acceptable carboxylic acid-terminated
polymers and their NPs have the potential to be developed into topical
formulations for the prevention and treatment of HSV infection.