TY - JOUR
T1 - Optimization of Small Molecules That Sensitize HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity
AU - Grenier, Melissa C.
AU - Ding, Shilei
AU - Vézina, Dani
AU - Chapleau, Jean Philippe
AU - Tolbert, William D.
AU - Sherburn, Rebekah
AU - Schön, Arne
AU - Somisetti, Sambasivarao
AU - Abrams, Cameron F.
AU - Pazgier, Marzena
AU - Finzi, Andrés
AU - Smith, Amos B.
N1 - Funding Information:
Equal contribution. A.F. designed the HTS screening. M.C.G. and A.B.S designed and synthesized analogs. W.D.T., R.S., and M.P. performed structural studies of analogs. S.D., D.V., and J.P.C. performed CBE and ADCC experiments. A.S. performed ITC experiments. M.C.G., A.F., and A.B.S. wrote the manuscript. All authors have read, edited, and approved the final manuscript. Funding was provided by Program Project (P01 GM 56550) to M.C.G., A.F., and A.B.S.; this work was also supported by an internal CRCHUM grant (for the HTS screening) awarded to A.F., by a CIHR foundation grant #352417 to A.F., and by a NIH R01 to A.F. and M.P. (AI129769) and to M.P. (AI116274). A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235. S.D. is the recipient of a FRSQ postdoctoral fellowship award. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, the Department of Defense, or the US Government. The authors declare no competing financial interest.
Funding Information:
Funding was provided by Program Project (P01 GM 56550) to M.C.G., A.F., and A.B.S.; this work was also supported by an internal CRCHUM grant (for the HTS screening) awarded to A.F., by a CIHR foundation grant #352417 to A.F., and by a NIH R01 to A.F. and M.P. (AI129769) and to M.P. (AI116274). A.F. is the recipient of a Canada Research Chair on Retroviral Entry # RCHS0235. S.D. is the recipient of a FRSQ postdoctoral fellowship award.
Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2020/3/12
Y1 - 2020/3/12
N2 - With approximately 37 million people living with HIV worldwide and an estimated 2 million new infections reported each year, the need to derive novel strategies aimed at eradicating HIV-1 infection remains a critical worldwide challenge. One potential strategy would involve eliminating infected cells via antibody-dependent cellular cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to conceal epitopes located in its envelope glycoprotein (Env) that are recognized by ADCC-mediating antibodies present in sera from HIV-1 infected individuals. Our aim is to circumvent this evasion via the development of small molecules that expose relevant anti-Env epitopes and sensitize HIV-1 infected cells to ADCC. Rapid elaboration of an initial screening hit using parallel synthesis and structure-based optimization has led to the development of potent small molecules that elicit this humoral response. Efforts to increase the ADCC activity of this class of small molecules with the aim of increasing their therapeutic potential was based on our recent cocrystal structures with gp120 core.
AB - With approximately 37 million people living with HIV worldwide and an estimated 2 million new infections reported each year, the need to derive novel strategies aimed at eradicating HIV-1 infection remains a critical worldwide challenge. One potential strategy would involve eliminating infected cells via antibody-dependent cellular cytotoxicity (ADCC). HIV-1 has evolved sophisticated mechanisms to conceal epitopes located in its envelope glycoprotein (Env) that are recognized by ADCC-mediating antibodies present in sera from HIV-1 infected individuals. Our aim is to circumvent this evasion via the development of small molecules that expose relevant anti-Env epitopes and sensitize HIV-1 infected cells to ADCC. Rapid elaboration of an initial screening hit using parallel synthesis and structure-based optimization has led to the development of potent small molecules that elicit this humoral response. Efforts to increase the ADCC activity of this class of small molecules with the aim of increasing their therapeutic potential was based on our recent cocrystal structures with gp120 core.
KW - Antibody-dependent cellular cytotoxicity (ADCC)
KW - high throughput screen (HTS)
KW - small molecule CD4 mimetic compounds (CD4mc)
KW - structure-activity relationships (SARs)
UR - http://www.scopus.com/inward/record.url?scp=85075625748&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.9b00445
DO - 10.1021/acsmedchemlett.9b00445
M3 - Article
AN - SCOPUS:85075625748
SN - 1948-5875
VL - 11
SP - 371
EP - 378
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 3
ER -