Blocking HIV Infection and Improving Bone Marrow Transplantation by Targeting Chemokine Receptors


Sakmar, Thomas

HIV-1, the virus that causes AIDS, infects certain immune system cells. In order to enter a cell, the virus must fasten itself to two receptors on the cell surface. First it binds to a receptor called CD4; then it attaches to either CXCR4 or CCR5. The role of CXCR4 and CCR5 as HIV-1 co-receptors was discovered in 1996. Inspired by that finding, Rockefeller biochemist Thomas P. Sakmar (1956- ) began developing small molecules that could seek out and bind to CXCR4 and CCR5 before HIV-1, thus preventing HIV-1 from getting into cells. He and his coworkers demonstrated the feasibility of small molecule HIV blockers and provided a foundation for the rational design and optimization of potential drug compounds. Others took this basic research into the clinic. A prototype HIV-1 blocker was tested in clinical trials at the Rockefeller Hospital. Two FDA-approved drugs have been developed as a result of Sakmar’s laboratory studies—one for treating HIV/AIDS, the other used in preparing certain patients for bone marrow transplants.

Sakmar had previously studied cellular receptors in another part of the body—light-sensing receptors in the eye’s retina. These receptors, and both CXCR4 and CCR5, belong to a large family of proteins with similar structures that snake back and forth through the cell membrane seven times. Such heptahelical receptors—also know as G protein-coupled receptors—comprise the largest gene family in the human genome. Heptahelical receptors are particularly important because they are the targets of more than a quarter of all therapeutic drugs.

Sakmar drew on his general knowledge of heptahelical receptors to better understand the biology of CXCR4 and CCR5, which are members of the chemokine receptor subfamily of heptahelical receptors. Many chemokine receptors, including CCR5, interact with immune-system signaling molecules during inflammation. The research of the Sakmar laboratory—including proof-of-concept, computational models, and laboratory studies to refine the design of prototype drugs—contributed to the development of Maraviroc™, released in 2007, and the first member of a new class of drugs to treat HIV/AIDS by blocking cellular entry targeting CCR5, rather than by fighting the virus from inside the cell after infection has occurred.

The search for a molecule to block CXCR4 led in a different direction. In addition to playing a role in the immune response, CXCR4 can affect cell adhesion and mobilization. Members of the Sakmar laboratory also studied a prototype for Mozobil™, which received FDA approval in 2008. By blocking CXCR4 function, this drug prevents stem cells from homing to the bone marrow, allowing them to be collected from a patient’s blood in advance of an autologous bone marrow transplant. The aim of targeting CCR5 and CXCR4 and understanding the biology of chemokine receptors relevant to HIV-1 continues to be a main focus of Sakmar’s research, along with studies of vision and the retina.

Thomas P. Sakmar received the AB from the University of Chicago (1978) and the MD from Chicago’s Pritzker School of Medicine (1982). He was then an intern and resident in internal medicine at Massachusetts General Hospital and a clinical fellow at Harvard Medical School. In 1985, Sakmar began postdoctoral research with H. Gobind Khorana (Nobel Prize, 1968) in the departments of biology and chemistry at the Massachusetts Institute of Technology. In 1990, he moved to Rockefeller as assistant professor and head of laboratory. He was promoted to tenured senior professor in 1998. From February 2002 to September 2003, he served as acting president of The Rockefeller University. He has received an Ellison Medical Foundation Senior Scholar Award for his research on age-related macular degeneration.

Selected Publications

Donzella GA, Schols D, Lin SW, Esté JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E, and Moore JP. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nature Med, 1998, 4: 72–77

Dragic T, Trkola A, Lin SW, Nagashima K, Kajumo F, Allaway G, Wu L, MacKay C, Sakmar TP, Maddon PJ, and Moore JP. N-Terminal substitutions in the CCR5 co-receptor impair gp120 binding and HIV-1 entry. J Virol, 1998, 72: 279–284
http://jvi.asm.org/cgi/reprint/72/1/279

Dragic T, Trkola A, Thompson DAD, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, and Moore JP. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci USA, 2000, 97: 5639–5644
http://www.pnas.org/content/97/10/5639.full.pdf+html

Tsamis F, Gavrilov S, Kajumo F, Seibert C, Kuhmann S, Ketas T, Trkola A, Palani A, Clader JW, Tagat JR, McCombie S, Baroudy B, Moore JP, Sakmar TP, and Dragic T. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry. J Virol, 2003, 77: 5201–5208
http://jvi.asm.org/cgi/reprint/77/9/5201

Seibert C and Sakmar TP. Small-molecule antagonists of CCR5 and CXCR4: A promising new class of anti-HIV-1 drugs. Curr Pharm Design, 2004, 10: 2041–2062

Billick E, Seibert C, Pugach P, Ketas T, Trkola A, Endres MJ, Murgolo NJ, Coates E, Reyes GR, Baroudy BM, Sakmar TP, Moore JP, and Kuhmann SE. The differential sensitivity of human and rhesus macaque CCR5 to small-molecule inhibitors of human immunodeficiency virus type 1 entry is explained by a single amino acid difference and suggests a mechanism of action for these inhibitors. J Virol, 2004, 78: 4134–4144
http://jvi.asm.org/cgi/reprint/78/8/4134

Seibert C, Ying W, Gavrilov S, Tsamis F, Kuhmann SE, Palani A, Tagat JR, Clader JW, McCombie SW, Baroudy BM, Smith SO, Dragic T, Moore JP, and Sakmar TP. Interaction of small molecule inhibitors of HIV-1 entry with CCR5. Virology, 2006, 349: 41–54

Further Reading

Sakmar TP. Twenty years of the magnificent seven: With decades of discovery on seven transmembrane receptors, why haven't we saved the day? The Scientist, 2005, 19(1): 22

Links

Thomas P. Sakmar, Laboratory of Molecular Biology and Biochemistry
http://www.rockefeller.edu/labheads/sakmar/sakmar-lab.html

FDA Approves Novel Antiviral Drug
http://www.fda.gov/bbs/topics/news/2007/new01677.html