Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

Amos B. Smith, III


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.

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