*11.1.2.1. PSC-RANTES*

PSC-RANTES, a potent synthetic inhibitor of the CCR5 co-receptor, had *in vitro*, showed antiviral activity against all HIV-1 subtypes as well as being able to inhibit the infection of Langerhans cells by HIV-1, which are considered crucial cells for HIV-1 transmission across the vaginal epithelium [210-212].

### *11.1.2.2. CMPD167*

CMPD167, a cyclopentane-based compound formulated as a 5 mmol vaginal gel, provided protection from vaginal simian/human immunodeficiency virus (SHIV) challenge in eight out of ten macaques [209], and, has been assessed in combination with two peptides that block the viral–host cell interaction at different loci, BMS-378806 and C52-L. BMS-378806 binds viral gp120 and prevents attachment to the CD4 and CCR5 receptors [213, 214], whereas C52-L, a modified version of enfuvirtide, inhibits gp41-mediated viral–cell fusion [209, 215]. Although these animal studies evaluating combinations of compounds with different mechanisms are promising, it is not yet clear whether they will correlate with protection from HIV-1 in human trials [209]. An important challenge in considering the CCR5 inhibitors for use as topical microbicides is their inability to block the entry of CXCR4-tropic virus. Although this latter pathway is less important in sexual transmission, it might still have a role in the infection process. Another concern is the pressure that CCR5-inhibiting compounds might place on HIV-1 to shift toward the use of non-CCR5 pathways/co-receptors to gain entry into cells. A clinically effective microbicide most likely will need to block all modes of receptor-mediated entry [191].

### *11.1.2.3. Cyanovirin-N*

Additionally, beyond the fusion inhibitor C52-L, which inhibits viral-cell gp41-mediated fusion [209, 215], another fusion inhibitor that is being evaluated in clinical trials as a topical microbicide is cyanovirin-N, the lectin purified compound from cyanobacterium. A cyano‐ virin-N, prevents viral–host cell fusion by binding high mannose residues in the HIV-1 envelope [216, 217]. However, it is necessary to consider that some lectins have shown unwanted side-effects, such as human red blood cell agglutination, mitogenic stimulation of peripheral blood mononuclear cells (PBMC), inflammatory activity, and cellular toxicity [218]. Various formulations of cyanovirin-N, including those expressed by lactobacilli, are under development [219] (Table 6).

#### **11.2. Non-specific microbicide agents**

#### *11.2.1. Vaginal milieu protectors/acidifying agents*

Vaginal milieu protectors are topical microbicides that promote the maintenance and restora‐ tion of natural protective mechanisms within the vaginal canal - the acidic pH maintained by lactobacilli. A pH between 4 0 and 5 8 has been shown to inactivate HIV-1 [220-222]. Therefore, various factors affecting this acidic pH, such as the presence of sêmen or bacterial vaginosis, neutralise the baseline acidity of the vagina. Use of microbicidal compounds in this class can act as direct acidifying agents, or as enhancers of lactobacilli production [220-224]. Some representatives of this class that have been evaluated in clinical studies are carbopol 974 (BufferGel®) [223, 224] and acidoform (Amphora®) [225, 226] (Table 6).
