To prevent the spread of HIV and other sexually transmitted diseases (STDs), researchers are working globally to develop new prevention options such as microbicides. Microbicides are innovative products that could be used vaginally or rectally to protect against STDs. There are several mechanisms of action that may permit microbicides to prevent HIV infection. These include killing or inactivating the virus, blocking the interaction between the virus and the target cell, strengthening the body’s natural defenses, or preventing infection from spreading to other cells. In order for a candidate microbicide to be successful, it must be safe, effective, inexpensive, and widely accepted.
Our efforts in the field of microbicide development include a microbicide testing service, which is sponsored by CONRAD (Arlington, VA). Our preclinical microbicide testing utilizes a screening algorithm to assess candidate microbicides for cytotoxicty and anti-HIV-1 activity. An ideal compound would have little or no in vitro cytotoxicity and fast-acting activity against multiple strains and subtypes of cell-free and cell-associated HIV-1. Investigations are also employed to evaluate combinations of two agents for additive or synergistic activity against HIV-1. The goal of this long-standing project is to identify compounds that have in vitro characteristics indicative of their potential as anti-HIV-1 microbicide agents. Between May 2001 and March 2012, over 1000 compounds were screened for CONRAD. A number of agents were shown to have high selectivity indices (little or no cytotoxicity and consistently high activity in all viral assays). These efforts will greatly facilitate the discovery of new compounds that can be used globally as microbicides.
Selected Publications (See all Shendra Passic's publications in PubMed. Also, see publications for Shendra Miller, published under maiden name.)
"Cationic cell penetrating peptides as potential inhibitors of HIV-1 infection"
Keogan S, Passic S, Wigdahl B, and F Krebs
Gender Medicine, 9(1):S94, 2012.
"Application and removal of polyanionic microbicide compounds enhance subsequent infection by HIV-1"
Pirrone V, Passic S, Wigdahl B, and FC Krebs
Virology Journal, 9: 33, 2012.
"Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment"
Li L, Aiamkitsumrit B, Pirrone V, Nonnemacher, MR, Wojno A, Passic S, Flaig K, Kilareski E, Blakey B, Ku J, Shah R, Martin-Garcia J, Moldover B, Servance L, Downie D, Lewis S, Jacobson JM, Kolson D, and B Wigdahl
J Neurovirol;17(1):92-109 (Epub Jan 12, 2011 ) Feb 2011.
"A styrene-alt-maleic acid copolymer is an effective inhibitor of both R5 and X4 human immunodeficiency virus type 1 infection"
Pirrone V, Passic SR, Wigdahl B, Rando RF, Labib M, and Krebs FC
Journal of Biomedicine and Biotechnology, 2010:548749. doi:10.1155/2010/548749, 2010
"Structure-activity relationships of polybiguanides with activity against human immunodeficiency virus type 1"
Passic SR, Ferguson ML, Catalone BJ, Kish-Catalone T, Kholodovych V, Zhu W, Welsh W, Rando R, Howett MK, Wigdahl B, Labib M, and Krebs FC
Biomedicine & Pharmacotherapy, 16:723-732, 2010
"Persistent interactions between the biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection"
Thakkar N, Pirrone V, Passic S, Keogan S, Zhu W, Kholodovych V, Welsh W, Rando R, Labib M, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, 54: 1965-1972, 2010
"Specific interactions between the viral co-receptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection"
Thakkar N, Pirrone V, Passic S, Zhu W, Kholodovych V, Welsh W, Rando RF, Labib ME, Wigdahl B, and Krebs FC
Antimicrobial Agents and Chemotherapy, 53: 631-638, 2009
"Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type 1 envelope pg120"
Gopi H, Umashankara M, Pirrone V, Lalonde J, Madani N, Tuzer F, Baxter S, Zentner I, Cocklin S, Jawanda N, Miller SR, Schön A, Klein JC, Freire E, Krebs FC, Smith AB, Sodroski J, and Chaiken I
Journal of Medicinal Chemistry, 51: 2638-2647, 2008
"Critical design features of phenyl carboxylate-containing polymer microbicides"
Rando RF, Obara S, Osterling MC, Mankowski M, Miller SR, Ferguson ML, Krebs FC, Wigdahl B, Labib M, and Kokubo H
Antimicrobial Agents and Chemotherapy, 50: 3081-3089, 2006
I"n vitro preclinical testing of nonoxynol-9 as potential anti-human immunodeficiency virus microbicide: a retrospective analysis of results from five laboratories"
Beer BE, Doncel GF, Krebs FC, Shattock RJ, Fletcher PS, Buckheit Jr. RW, Watson K, Dezzutti CS, Cummins JE, Bromley E, Richardson-Harman N, Pallansch LA, Lackman-Smith C, Osterling C, Mankowski M, Miller SR, Catalone BJ, Welsh PA, Howett MK, Wigdahl B, Turpin JA, and Reichelderfer P
Antimicrobial Agents and Chemotherapy, 50: 713-723, 2006
"Polybiguanides, particularly polyethylene hexamethylene biguanide, have activity against human immunodeficiency virus type 1"
Krebs FC, Miller SR, Ferguson ML, Labib M, Rando RF, and Wigdahl B
Biomedicine & Pharmacotherapy, 59: 438-445, 2005
"Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G"
Catalone BJ, Miller SR, Ferguson ML, Malamud D, Kish-Catalone T, Thakkar NJ, Krebs FC, Howett MK, and Wigdahl B
Biomedicine & Pharmacotherapy, 59: 430-437, 2005
"Comparative safety evaluation of the candidate vaginal microbicide C31G"
Catalone BJ, Kish-Catalone TM, Neely EB, Budgeon LR, Ferguson ML, Stiller C, Miller SR, Malamud D, Krebs FC, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 49: 1509-1520, 2005
"Prolonged exposure to the candidate microbicide C31G differentially reduces cellular sensitivity to agent re-exposure"
Catalone BJ, Ferguson ML, Miller SR, Malamud D, Kish-Catalone T, Thakkar NJ, Krebs FC, Howett MK, and Wigdahl B
Biomedicine & Pharmacotherapy, 59: 460-468, 2005
"Comparative in vitro sensitivities of human immune cell lines, vaginal and cervical epithelial cell lines, and primary cells to candidate microbicides nonoxynol 9, C31G, and sodium dodecyl sulfate"
Krebs FC, Miller SR, Catalone BJ, Fichorova R, Anderson D, Malamud D, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 46: 2292-2298, 2002
"Sodium dodecyl sulfate and C31G as microbicidal alternatives to nonoxynol-9: comparative sensitivity of primary human vaginal keratinocytes"
Krebs FC, Miller SR, Catalone BJ, Welsh PA, Malamud D, Howett MK, and Wigdahl B
Antimicrobial Agents and Chemotherapy, 44: 1954-1960, 2000 |