Abstract
Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. Previously, we reported that the polysulfonic compound ADS-J1 is a potential candidate microbicide that not only inhibits HIV-1 entry, but also seminal fibrils. However, the carcinogenic azo moieties in ADS-J1 preclude its clinical application. Here, we screened several ADS-J1-like analogs and found that the antiparasitic drug suramin most potently inhibited seminal amyloid fibrils. Using various biochemical methods, including Congo red staining, CD analysis, transmission EM, viral infection assays, surface plasmon resonance imaging, and molecular dynamics simulations, we investigated suramin's inhibitory effects and its putative mechanism of action. We found that by forming a multivalent interaction, suramin binds to proteolytic peptides and mature fibrils, thereby inhibiting seminal fibril formation and blocking fibril-mediated enhancement of viral infection. Of note, suramin exhibited potent anti-HIV activities, and combining suramin with several antiretroviral drugs produced synergistic effects against HIV-1 in semen. Suramin also displayed a good safety profile for vaginal application. Moreover, suramin inhibited the semen-derived enhancer of viral infection (SEVI)/semen-mediated enhancement of HIV-1 transcytosis through genital epithelial cells and the subsequent infection of target cells. Collectively, suramin has great potential for further development as a combination microbicide to reduce the spread of the AIDS pandemic by targeting both viral and host factors involved in HIV-1 sexual transmission.
Highlights
Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs
In an attempt to identify an active compound that acts as a multifunctional microbicide with a safer profile than ADS-J1, we noticed a series of commercially available suramin-like compounds with similar molecular weights, and degrees of sulfation, to ADS-J1, but without clear harmful bonds (Fig. 1, A–G)
The thioflavin T (ThT) assay and the Congo red– binding assay are two fast and conventional methods used to detect amyloid fibrils. Because several of these compounds could induce an increase in the fluorescence intensity of ThT, we applied the Congo red– binding assay to test their inhibitory effects on PAP248 –286 aggregation
Summary
Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. PAP248 –286 self-aggregates to form an amyloid fibril named semen-derived enhancer of viral infection (SEVI), which is the best-characterized seminal amyloid [3] These proteolytic fragments contain several basic residues, which renders these fibrils very cationic with the ability to capture HIV-1 virions, promote viral attachment to target cells, and augment viral fusion [3]. ADS-J1 displayed synergetic effects with ARV drugs on inhibiting viral infection in semen This dual-function agent, which targets both virus and seminal amyloid fibrils, represents an alternative option to design a combination candidate microbicide.
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