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Principal Investigator: IRWIN M CHAIKEN
Organization: DREXEL UNIVERSITY
Fiscal Year: 2022
Award: $343,785
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
HIV-1 is the causative agent of AIDS, which remains a global pandemic. The need continues for more effective
and broadly active preventive strategies and anti-retroviral therapies to target infectious virus and already-
infected cells. In both virus-cell and cell-to-cell infection, the metastable, virus-specific envelope protein (Env)
is activated by cell receptors to enable entry and disease progression. The underlying hypothesis driving
Project 4 of this Program Project is that the conserved sites in Env gp120 and the conformational metastability
of the Env gp120-gp41 trimer spike can be used as “Achilles’ heels” to target both HIV-1 virus and virus-
infected cells. The project will be underpinned initially by a class of peptide triazole (PT) Env antagonists that
[1] target a specific gp120 site overlapping the conserved CD4 binding site, [2] suppress gp120 interactions at
both of the cell receptor binding sites, [3] drive Env gp120 into an inactivated conformation and [4], upon
treatment of HIV-1, cause gp120 shedding and irreversibly inactivate the virus. The work will be stimulated by
a major recent breakthrough with the discovery of more drug-like small cyclic PTs (cPTs) that retain the
functional signature of the original linear PTs but with massively increased proteolytic resistance. cPT variants
with expanded chemical space for future structural variation have also been discovered. A major goal in this
project going forward is to advance designs for cPTs through synthesis and mechanistic definition of cPT-Env
encounter. We will seek to expand understanding of mechanisms by which cPTs inactivate viruses and Env-
expressing cells through Env spike trimer interactions, and seek to integrate this understanding with the
evolving definition of Env trimer structures and conformational states. Investigations of cPT inhibitors will
examine the notion that PTs and cPTs can hijack the intrinsic conformational metastability properties of the
Env protein and the associated metastability of the virus. The successful derivation and properties of cPTs will
be used as a springboard to derive new structure-minimized surrogates targeting the conserved region of the
gp120 subunits of Env where cPTs bind. In addition, the combined macrocycle-to-peptidomimetic approach will
be used to derive antagonists against more diverse Env trimer epitopes for neutralizing the virus. We will relate
the mechanisms of peptidomimetic/macrocyclic inhibitors with those for other small molecule inhibitors
investigated in this Program. The investigations of Project 4 will address all four broad specific aims of the
Program Project team, namely to identify inhibitors of HIV-1 Env, to determine their interaction mechanisms
with Env proteins, to determine their effects on virus and cell Env protein trimers and to determine the potential
for virus resistance.
Terms: <AIDS><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunologic Deficiency Syndrome><Address><Antigenic Determinants><Automobile Driving><Binding><Binding Determinants><Binding Sites><Cell Body><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Characteristics><Chemicals><Combining Site><Cyclic Peptides><Cyclicity><Data><Derivation><Derivation procedure><Disease Progression><Drugs><Envelope Protein><Epitopes><Future><Genetic Alteration><Genetic Change><Genetic defect><Glycoproteins><Goals><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV1><HTLV-III gp120><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Infection><Intervention><Intervention Strategies><Investigation><Medication><Membrane><Modeling><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mutation><Outcome><Pathogenesis><Peptides><Periodicity><Pharmaceutic Preparations><Pharmaceutical Preparations><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Property><Protein Conformation><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><Reactive Site><Receptor Cell><Research Grants><Research Project Grants><Research Projects><Resistance><Rhythmicity><Site><Structure><Structure-Activity Relationship><Testing><Triazoles><Variant><Variation><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Work><antagonist><anti-retroviral therapy><anti-retroviral treatment><antiretroviral therapy><antiretroviral treatment><base><cell envelope><chemical structure function><conformation><conformational state><design><designing><driving><drug/agent><env Antigens><env Gene Products><env Polyproteins><env Protein><experiment><experimental research><experimental study><genome mutation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><inhibitor><interventional strategy><membrane structure><neutralizing antibody><pandemic><pandemic disease><peptide mimetic><peptide mimic><peptidomimetics><pharmacophore><programs><protein complex><resistant><small molecule><small molecule inhibitor><structure function relationship><viral resistance><virus envelope><virus protein><virus resistance>