Date of Award
Doctor of Philosophy (PhD)
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.
Gaffney, Althea Erica, "The Design And Synthesis Of Inhibitors Of Hiv-1 Viral Entry And Photoaffinity Labeled Probes For Structural Elucidation Of The Hiv-1 Env" (2019). Publicly Accessible Penn Dissertations. 3572.