The pathogenesis of Gram-negative septic shock, a leading cause of mortality in critically ill patients, is a consequence of the overwhelming innate immune response to endotoxins, or lipopolysaccharides (LPS), present on the surface of Gram-negative bacteria (including Category A and B Select Agents). We have shown that relatively simple and synthetically easily accessible molecules of the lipopolyamine class specifically bind to the toxic """"""""Lipid A"""""""" moiety of LPS and neutralize its toxicity. Extensive structure-activity relationship studies on lipopolyamines using a combination of classical medicinal chemistry approaches, combinatorial lead generation, molecular modeling, high-throughput screening, and the development of novel secondary and tertiary-level assays to verify the premise of true sequestration of LPS by these compounds in vitro as well as in animal models have led to the identification of DS-96, an N- alkylhomospermine derivative. The in vitro and in vivo LPS-sequestering and -neutralizing properties of DS- 96 rival that of polymyxin B, a gold standard LPS sequestrant in every respect thus far. Importantly, in all of our in vivo studies to date, we have been unable to detect any apparent toxicity for DS-96. We propose to further the preclinical development of DS-96, establish efficacy in alternate animal models of endotoxic shock, characterize its safety profile, and obtain detailed pharmacokinetic and ADME data.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI077947-03
Application #
7777823
Study Section
Special Emphasis Panel (ZAI1-TP-M (J1))
Program Officer
Korpela, Jukka K
Project Start
2008-04-15
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$357,709
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Osaka, Ichie; Hefty, P Scott (2014) Lipopolysaccharide-binding alkylpolyamine DS-96 inhibits Chlamydia trachomatis infection by blocking attachment and entry. Antimicrob Agents Chemother 58:3245-54
Sil, Diptesh; Heinbockel, Lena; Kaconis, Yani et al. (2013) Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines. Open Biochem J 7:82-93
Martínez de Tejada, Guillermo; Sánchez-Gómez, Susana; Rázquin-Olazaran, Iosu et al. (2012) Bacterial cell wall compounds as promising targets of antimicrobial agents I. Antimicrobial peptides and lipopolyamines. Curr Drug Targets 13:1121-30
Schuerholz, Tobias; Dömming, Sabine; Hornef, Mathias et al. (2012) Bacterial cell wall compounds as promising targets of antimicrobial agents II. Immunological and clinical aspects. Curr Drug Targets 13:1131-7
Day, Timothy P; Sil, Diptesh; Shukla, Nikunj M et al. (2011) Imbuing aqueous solubility to amphotericin B and nystatin with a vitamin. Mol Pharm 8:297-301
Warshakoon, Hemamali J; Burns, Mark R; David, Sunil A (2009) Structure-activity relationships of antimicrobial and lipoteichoic acid-sequestering properties in polyamine sulfonamides. Antimicrob Agents Chemother 53:57-62
Wu, Wenyan; Sil, Diptesh; Szostak, Michal L et al. (2009) Structure-activity relationships of lipopolysaccharide sequestration in guanylhydrazone-bearing lipopolyamines. Bioorg Med Chem 17:709-15
Shrestha, Anurupa; Sil, Diptesh; Malladi, Subbalakshmi S et al. (2009) Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines. Bioorg Med Chem Lett 19:2478-81
Nguyen, Thuan B; Kumar, E V K Suresh; Sil, Diptesh et al. (2008) Controlling plasma protein binding: structural correlates of interactions of hydrophobic polyamine endotoxin sequestrants with human serum albumin. Mol Pharm 5:1131-7