Natural compounds against HIV
It is estimated that over 34 million people are still living with HIV worldwide. Although the introduction of highly active antiretroviral therapy (HAART) has considerably reduced HIV-related mortality, it does not achieve complete viral clearance. Furthermore, it is associated with toxicity and resistance issues. Various efforts to prevent HIV transmission have focused on the development of prophylactic vaccines and topical HIV microbicides, with limited success. Innovative approaches are urgently required to identify new anti-HIV molecules for prevention and therapy. The EU-funded PEPTHIV (Host defence peptides from neuroendocrine cells as a new source of anti-HIV compounds) project focused on the discovery of natural HIV inhibitors. Emphasis was given on host defence peptides (HDPs), important components of the innate immune system that serve as antimicrobials against a broad spectrum of pathogens. HDPs constitute an exciting class of drug candidates as they are unlikely to induce drug resistance. However, technical issues have hampered systematic screens for naturally occurring anti-HIV compounds. PEPTHIV focused on unique organelles of neuroendocrine cells that store secretory products upon secretion. These secretory granules are particularly enriched in HDPs and therefore, constitute an excellent model to screen new anti-HIV compounds. Researchers identified a peptide lead compound that showed considerable efficacy at repressing HIV replication by inhibiting the HIV protease. Additional molecules based on the structure of this compound were synthesised and demonstrated improved efficacy and complete lack of toxicity. This suggests that structure modification of HDPs is not only possible but vastly extends the range of available anti-HIV compounds and their specificity. Considering the lack of safe and efficient anti-HIV microbicides available to date, the PEPTHIV findings open new avenues for anti-HIV strategies. Results validate the potential of HDPs as peptide-based drugs, either directly as a microbicide against HIV or indirectly to target HIV protease in a similar approach to HAART.
Keywords
HIV, PEPTHIV, HDP, neuroendocrine cells, secretory granules
