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DC-SIGN Inhibitors for the Treatment of HIV Infection

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2013 / STTR
Agency Tracking Number:
R41AI106719
Solicitation Year:
2013
Solicitation Topic Code:
NIAID
Solicitation Number:
PA12-089
Small Business Information
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
3805 OLD EASTON RD DOYLESTOWN, PA 18902-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 1
Fiscal Year: 2013
Title: DC-SIGN Inhibitors for the Treatment of HIV Infection
Agency: HHS
Contract: 1R41AI106719-01
Award Amount: $300,000.00
 

Abstract:

DESCRIPTION (provided by applicant): DC-SIGN (dendritic cell specific ICAM-3-grabbing non-integrin), a membrane protein of C-type lectin family, is found in high levels on monocyte-derived DCs, some macrophages, and activated B cells. In vivo, DC-SIGN- positive cells were demonstrated in lymph nodes, tonsils, skin, and the subepithelial region of the cervix. DC- SIGN has been shown to bind to a number of viruses, mycobacteria, and the protozoan parasite Leishmania. Specifically, DC-SIGN has been identifiedas the dendritic cell receptor for human immunodeficiency virus (HIV-1 and HIV-2), simian immunodeficiency virus (SIV), dengue virus, Marburg virus, hepatitis C, Ebola, and cytomegalovirus. With respect to HIV-1 transmission, DC-SIGN has been shown to serve as ligand that efficiently binds, concentrates, and mediates transfer of virus from the mucosal surface to CD4+ T cells. Subepithelial DCs expressing DC-SIGN have been demonstrated to play important roles in cervicovaginal transmission of HIV-1. Along this line, several other studies have examined the process of DC-SIGN-mediated transmission of various pathogens and have suggested that targeting this cell surface molecule may serve as potential therapeutic strategy. DC-SIGN binds to high mannose and fucose moieties present on the HIV envelope glycoprotein gp120 with high affinity. Blocking this interaction at the site of primary infection could potentially be prophylactic and/or a potent microbicidal target. Both RNA interference and carbohydrate-bindingagents have been shown as potential means to inhibit DC-SIGN-mediated transmission of HIV-1. RNA-based therapies; however, present obstacles with respect to delivery, stability and potency. Similarly, converting carbohydrate leads to effective inhibitors could be challenging. Recently HTS screening of small molecule library has been reported to produce micromolar to sub-micromolar noncarbohyrate hits to block DC-SIGN and GP120 interaction. This validated the notion that HTS of noncarbohyrate library can produce micromolar noncarbohydrate hits. To maximize the chance of success, we will look for non-carbohydrate hits from three sources: HTS of in-house library, virtual screening of Zinc database, and binding-site directed lipophilic mining approach. The Specific Aims of this proposal are to 1) Discover a non-carbohydrate small molecule hit with micromolar binding activity to block the interaction of DC-SIGN and GP120; and 2) The hits from Aim 1 will be clustered and prioritized into ~3 chemotypes which willbe investigated and validated by examining the activity of structural variants prepared by synthesis or acquired from commercial sources. At the end of Phase 1, we will have identified at least one advanced drug- like hit with noncarbohydrate structure that blocks gp120 binding to DC-SIGN, exemplified by key representative members that are of sufficient interest for a full program of study in Phase 2. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Currently, gt33 million people are living with HIV, with 2.0 million deaths and 2.7 new cases in the year 2007. DC-SIGN (dendritic cell specific ICAM-3-grabbing non-integrin), a membrane protein of C-type lectin family, is found in high levels on monocyte-derived DCs, some macrophages, and activated B cells. Blockade of the binding of gp120 found on the cell surface of HIV-1 to DC-SIGN prevents internalization of HIV-1 and infection. We here describe the use of an innovative and validated screening paradigm to discover new agents that inhibit the HIV/gp120 interaction for eventual use for the treatment of HIV, either as monotherapy or in combination with other agents acting by different mechanistic pathways.

Principal Investigator:

Allen B. Reitz
215-589-6435
areitz@fc-cdci.com

Business Contact:

Allen Reitx
215-589-6435
areitz@fc-cdci.com
Small Business Information at Submission:

FOX CHASE CHEMICAL DIVERSITY CENTER, INC
3805 OLD EASTON RD DOYLESTOWN, PA 18902-

EIN/Tax ID: 126365221
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
Research Institution Information:
DREXEL UNIVERSITY
DREXEL UNIVERSITY
OFFICE OF RESEARCH 3201 ARCH STREET Suite 100
PHILADELPHIA, PA 19104-
Contact: