*11.2.1.1. Carbopol 974P*

receptor antagonist have been studied as topical microbicides, the PSC-RANTES [208] and

152 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

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

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

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

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

CMPD167 [209].

*11.1.2.1. PSC-RANTES*

*11.1.2.2. CMPD167*

entry [191].

*11.1.2.3. Cyanovirin-N*

development [219] (Table 6).

**11.2. Non-specific microbicide agents**

*11.2.1. Vaginal milieu protectors/acidifying agents*

the vaginal epithelium [210-212].

Different studies on the efficacy of carbopol 974P (BufferGel®) as topical microbicide have been conducted. The compound is a polyacrylic acid that buffers twice its volume of semen to a pH of 5 or less, and has shown spermicidal activity [223], virucidal *in vitro* activity to HIV-1 [221] and herpes simplex virus (HSV) [227], and protection in mouse vaginal models against HSV and *C. trachomatis* [224]. In gel form, inhibits human papillomavirus (HPV) in animal models [228]. Their safety, as topical microbicide, has also been demonstrated in clinical trials phase I [229, 230]. BufferGel was safe and acceptable among men in a penile tolerance study in HIV-1 infected and uninfected men [231], and a study of phase II/IIb (HPTN 035), showed safety and efficacy when compared with a placebo gel and with condoms.

## *11.2.1.2. Acidoform*

Acidoform (Amphora®) is a sexual lubricant, however, acid-buffering and its bioadhesive properties make it appealing for development as a microbicide candidate. Acidform has undergone two phase I safety studies, as well as the male penile tolerance study [232-234]. Clinical studies have shown that acidoform is well tolerated when used alone, and in combi‐ nation with nonoxinol 9 (N-9) compound, promotes vaginal irritation (80). The presence of moderate vulvar irritation, including itching, tingling, burning, dryness, erythema, ulceration, and vesicles, have been presented, but are instances considered mild [232, 233].

#### *11.2.2. Entry inhibitors*

Advances in the drug development against HIV-1 have lead to the identification of new compounds which could be used to target cellular entry and nuclear integration of virus in addition to drugs that commonly target RT and protease. Cellular entry of HIV-1 is a multistep procedure involving a range of cellular and molecular interactions between virus envelope protein and receptors expressed on the surface of the target cells, thus provid‐ ing many opportunities to block infection [235]. Topical microbicide agents of class entry inhibitors act by blocking the binding of HIV-1 to host cells, as well as inhibit fusion of the viral membranes. This class, stand out as anionic polymers microbicide agents, in which they present negative charges in their structure, interact with viral envelope proteins (gp120 and/or gp41) which interfers with attachment of HIV-1 to CD4+ cells [236]. The gp120 protein of CXCR4-tropic viruses are vulnerable to the actions of anionic polymers by changing the melting capacity of these viruses in the host cell membranes. However, there is controversy about the effectiveness of anionic polymers for CCR5-tropic viruses [236, 237]. Naphthalene sulphonate [238], carrageenan [239], cellulose sulphate [240], cellulose acetate phthalate [241], and dendrimers [242], are the main compounds evaluated in clinical trials, phase l, ll and lll (Table 6)*.*

#### *11.2.2.1. Naphthalene sulphonate*

Naphthalene sulphonate (PRO2000® gel), is a sulphfonated polymer with *in vitro* activity against HIV-1, *C. trachomatis*, *N. gonorrhoeae*, and HSV [243, 244]. Phase I clinical trials have shown that naphthalene sulphonate gel was generally well tolerated [238, 245]. Phase ll/llb revealed safety and efficacy, and a phase III efficacy trial, show that the naphthalene sulpho‐ nate gel has better efficacy when compared with BufferGel, gel placebo, or the condom [238, 244, 246].
