Abstract - Jacob Immel
Targeting Viral RNA: Developing a Novel Packaging Inhibitor for HIV-1
Jacob R. Immel1, Anuradha Roy2, Steven Bloom1
1Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS, USA; 2Director of COBRE CBID Infectious Disease Assay Development Core Facility, The University of Kansas, Lawrence, KS, USA
The Human Immunodeficiency Virus 1 (HIV-1), the causative agent of AIDS, is a deadly virus affecting millions of people worldwide. The virus infects and depletes healthy T-lymphocytes, crippling the immune system and leaving the body defenseless against opportunistic infections. Enormous effort has been made to develop anti-HIV drugs, but the heightened propensity for HIV-1 to adopt resistance conferring mutations continually limits their efficacy. One way to avoid HIV-1 drug resistance would be to target conserved aspects of the virus which are essential for viral replication but that cannot tolerate mutations. One example is ΨRNA, a critical region of viral RNA that drives the selective packaging of the complete HIV-1 genome (gRNA) into newly formed virions. Specifically, the Stem-loop 3 (SL3) of viral ΨRNA interacts with the nucleocapsid protein 7 (NCp7) domain of the viral Gag-polyprotein. Mutations in SL3 greatly impede the ability of NCp7 to correctly distinguish gRNA from other subcellular RNAs. This leads to new daughter virions that package non-genomic RNA and are, therefore, not infective. Thus, SL3 of ΨRNA stands out as a prime target for designing a mutation-resistant antiretroviral drug.
Recent work has shown that the high-fidelity interaction between NCp7 and SL3 is governed by a series of single-stranded guanosines located in the stem of SL3. These guanosines serve as a primary recognition element for NCp7 binding. Therefore, drugs that specifically target the stem of SL3 and impede NCp7 binding could offer a new approach to combat HIV-1 drug resistance, but no such drugs exist. To discover an effective NCp7-SL3 inhibitor, we used in silico modeling and synthetic peptide chemistry developed by our lab to design brand-new peptides to specifically engage SL3. Preliminary in vitro testing revealed that our novel peptides greatly diminished the infectivity of two major strains of HIV-1 and their daughter virions. Our peptides did not inhibit other stages of the HIV-1 lifecycle, consistent with their potential anti-packaging activity.