An estimated 38 million people globally are currently living with Human Immunodefficiency Virus (HIV-1). While HIV-1 can be effectively treated with antiretroviral therapy (ART), the efficacy of ART is challenged by its cost, required access to regular care, and the onset of viral resistance. Methods to both prevent and cure HIV-1 infection are thus desperately needed. Three such strategies are described herein. Firstly, small molecules which mimic CD4 have been developed which inhibit HIV-1 infection. Notably, these compounds increase the ability of the Env trimer to sample a more open conformation which sensitizes the Env to antibody mediated neutralization and elimination (ADCC). Secondly, HIV-1 infection inhibition and lysis of HIV-1 virions has been accomplished via the design, synthesis and validation of a family of small molecule “Dual-Action Virucidal Entry Inhibitors” (DAVEIs). These compounds, comprised of a small molecule warhead tethered to a segment of the gp41 MPER denoted Trp3, have achieved irreversible lytic inactivation of HIV-1 virions. Finally, small molecules appended with photoactivatable crosslinking moieties were developed which stabilize the Env conformation recognized by most broadly neutralizing antibodies. Importantly, no structure of this Env conformation is reported in the literature. This work is expected to enable both structural elucidation of this critical Env conformation and aid the development of an HIV-1 vaccine.