title: Novel Acylguanidine-Based Inhibitor of HIV-1.
abstract: The emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibits in vitro replication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24(Gag) production was unaffected, but virion release (measured as extracellular p24(Gag)) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity.
  
  
  
  New inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to prevent Env expression at the infected cell surface. Partial resistance to SM111 is mediated by mutations in Vpu and/or Env, suggesting that the compound affects host/viral protein interactions that are important during viral egress. Further characterization of SM111 and similar compounds may allow more detailed pharmacological studies of HIV-1 egress and provide opportunities to develop new treatments for HIV-1.
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Philip
authors: P
authors: Mwimanzi
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, Canada.
authors: Ian
authors: I
authors: Tietjen
authors: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, Canada.
authors: Scott C
authors: SC
authors: Miller
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Aniqa
authors: A
authors: Shahid
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Kyle
authors: K
authors: Cobarrubias
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Natalie N
authors: NN
authors: Kinloch
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors: Bemuluyigza
authors: B
authors: Baraki
authors: Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, Canada.
authors: Jonathan
authors: J
authors: Richard
authors: Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, Canada.
authors: Andrés
authors: A
authors: Finzi
authors: Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, Canada.
authors: David
authors: D
authors: Fedida
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors: Zabrina L
authors: ZL
authors: Brumme
authors: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada Department of Molecular Biology and Biochemistry, Faculty of Sciences, Simon Fraser University, Burnaby, Canada mark_brockman@sfu.ca.
authors: Mark A
authors: 0000-0001-6432-1426
authors: MA
authors: Brockman
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics; D015704:CD4 Antigens / Q000235:genetics; D002460:Cell Line; D058851:GPI-Linked Proteins / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009154:Mutation / Q000187:drug effects; D014771:Virion / Q000187:drug effects; D057074:Virus Release / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D015704:CD4 Antigens; D058851:GPI-Linked Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2