The advent of effective combination antiretroviral therapies (cART) has increased the life expectancy for HIV-1
patients, however, these patients are still prone to comorbidities, such as HIV-associatiated neurocognitive
disorders (HAND), which affect up to 50% of HIV-infected individuals. Persistent inflammation due to the
overactivation of the innate immune system is one of the main underlying causes of HAND. Nucleotide binding
domain, leucine rich repeat pyrin domain containing protein-3 (NLRP3) inflammasome has emerged as a
druggable target for the management of HIV-1-associated neuropathologies. The NLRP3 inflammasome is
shown to be activated in response to a wide array of pathogen- and danger-associated molecular patterns
(PAMPs and DAMPs, respectively). A key step in the activation process is a homotypic interaction between the
pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD
(ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1¿ (IL-1¿) and
IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as
MCC950, is reported to display beneficial effects in the transgenic mouse models. Our recent studies identified
a small molecule, AMS-17, that thwarted the NLRP3 activation in N9 microglia both in vitro and in vivo.
Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability
to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is
focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high drug-likeness.
Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical
characterization of AMS-17 analogues. Aim 2 will involve testing of the lead candidates in the humanized mouse
model of HAND. The proposed studies are highly significant since they will provide new therapeutic options to
minimize HIV-associated neurocognitive dysfunction. The proposal incorporates expertise in the area of
synthetic medicinal chemistry (Dr. Kulkarni), biological screening (Dr. Bukrinsky), and computer-assisted drug
design (Dr. Adzhubei). It is fully consistent with the goals of this RFA and is expected to define NLRP3 inhibitory
compounds working through a novel mechanism different from that of any other currently used drug.