Acrosin inhibitor, 4'-acetamidophenyl 4-guanidinobenzoate, an experimental vaginal contraceptive with anti-HIV activity.

ABSTRACT

Serine proteases are involved in a wide variety of seemingly unrelated physiological functions including capacitation of the spermatozoa and potentiation of human immunodeficiency virus (HIV) infection. The experimental vaginal contraceptives derived from 4-guanidinobenzoic acid act through inhibition of acrosin--a serine protease from the sperm. The serial ten-fold dilutions of 4'-acetamidophenyl 4-guanidinobenzoate (AGB) were tested in vitro for the effect against HIV infection by assaying the suppression of de novo p24 synthesis in virus-inoculated MT-4 T lymphocytes. The results reveal that complete inhibition of HIV occurred at 100 micrograms/ml--a dose corresponding to previously reported concentrations responsible for preventing fertilization in rabbits. These findings suggest that serine protease inhibitors and in particular the guanidinobenzoates, reported to be up to 100-fold more potent and less irritating than nonoxynol-9, can be potentially operative against sexual transmission of HIV.

ABSTRACT

PIP Biochemists at the New York University Medical Center assayed suppression of de novo p24 synthesis in HIV-inoculated MT-4 T lymphocytes to compare the effects of 4'-acetamidophenyl 4-guanidinobenzoate hydrochloride (AGB), Nalpha-p-tosyl-L-lysine chloro methyl ketone (TLCK), and nonoxynol-9 against HIV infection. Specifically, they wanted to determine the possibility that AGB, an antagonist of acrosin (a serine protease critical to sperm capacitation and to fortification of HIV infection), could launch a new class of vaginal spermicidal agents with anti-HIV activity. 100 mcg/ml AGB (a nontoxic dose) induced complete inhibition of HIV but did not affect the viability of MT-4 T lymphocytes. AGB had a 100 times more potent effect against HIV and had a lower cytotoxic effect (i.e., less irritating) than nonoxynol 9. These findings suggest that serine protease inhibitors, especially the guanidinobenzoates, have the potential to be effective vaginal contraceptives with anti-HIV activity.