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UCI Faculty Profile
The acquired immune deficiency syndrome (AIDS) is of worldwide importance. The research in the laboratory has concentrated on anti-HIV drug development and the roles various HIV proteins play in the retroviral life cycle. Working with
organic chemists, we are developing new anti-HIV compounds that target a specific viral protein called integrase. Integrase is absolutely required for HIV replication and has no mammalian homolog. Furthermore, integrase is the third of three viral enzymes and the only enzyme for which there are currently no inhibitors used to treat patients. To date, we have identified well over 100 compounds that inhibit HIV integrase; some of these rival the most potent small molecule inhibitors of HIV integrase yet described. In addition to drug discovery, we are using these compounds as tools to better understand the molecular mechanisms involved in HIV integrase function and retroviral integration. In particular we are studying the effects of inhibitor resistance mutations on HIV replication. We are also attempting to identify the amino acids that comprise the inhibitor-binding pocket on the integrase protein. Continued synthesis of anti-HIV compounds is ongoing, especially compounds that inhibit primary clinical isolates of HIV and both North American and African isolates. Techniques that are in use in the laboratory include molecular biological techniques, the polymerase chain reaction (PCR), quantitative real-time PCR, and live HIV replication studies using clinical isolates of HIV and tissue culture adapted HIV strains. Recent collaborative work has been initiated that includes structural biology of integrase and drug discovery against several other HIV proteins, including the "negative factor", Nef, and the "viral infectivity factor", Vif. Studies on the role of antimicrobial peptides in the pathogenesis of HIV and simian immunodeficiency virus (SIV) infections are also underway.
Recent Publications from the Robinson Laboratory:
- King, P.J. and Robinson, W.E.,
Jr. Resistance to the anti-human immunodeficiency virus type
1 compound L-chicoric acid results from a single mutation at
amino acid 140 of integrase. J. Virol. 72:8420-8424 (1998).
- King, P.J., Ma, G.X., Miao, W., Jia, Q., McDougall,
B.R., Reinecke, M.G., Cornell, C., Kuan, J., Kim, T., and Robinson,
W.E., Jr.Structure-activity relationships: Analogues of the dicaffeoylquinic
and dicaffeoyltartaric acids as potent inhibitors of human
immunodeficiency virus type 1 integrase and replication. J.
Med. Chem. 42:497-509,
1999.
- Reinke, R., Steffen, N.R., and Robinson, W.E., Jr. Natural
selection results in conservation of HIV-1 integrase activity
despite sequence variability. AIDS 15:823-830, 2001.
- Reinke, R.A., King, P.J., Victoria, J.G., McDougall, B.R.,
Ma, G., Mao, Y., Reinecke, M.G., and Robinson, W.E.,
Jr. Dicaffeoyltartaric acid analogues inhibit human immunodeficiency
virus type 1
(HIV-1) integrase and HIV-1 replication at non-toxic concentrations.
J. Med. Chem. 45:3669-3683, 2002.
- Reinke, R.A., Lee, D.J., and Robinson, W.E., Jr. Inhibition
of human immunodeficiency virus type 1 isolates by the integrase
inhibitor, L-731,988, a diketo acid. Antimicrob. Agents Chemother.
46:3301-3303, 2002.
- King, P.J. Lee, D.J., Reinke, R.A., Victoria, J.G., Beale,
K.K., and Robinson, W.E., Jr. Human immunodeficiency virus
type-1 integrase containing a glycine to serine mutation at
position 140 is attenuated for catalysis and resistant to
integrase
inhibitors.
Virology 306:146-161 (2003).
- Victoria, J.G., Lee, D.J.,
McDougall, B.R., and Robinson, W.E., Jr. Replication kinetics
for divergent type 1 human
immunodeficiency
viruses using quantitative SYBR green I real-time polymerase
chain reaction. AIDS Res. Human Retroviruses 19:865-874 (2003).
- Kuznetsov,
Y.G., Victoria, J., Robinson, W.E., Jr., and McPherson, A.
Atomic force microscopy investigation of HIV
and HIV-infected
lymphocytes. J. Virol. 77:11896-11909 (2003).
- Lee, D.J.
and Robinson, W.E., Jr. Human immunodeficiency virus type
1 (HIV-1) integrase: resistance to diketoacid
integrase
inhibitors impairs HIV-1 replication, integration, and confers
cross-resistance to L-chicoric acid. J. Virol. 78:5835-5847
(2004).
- Reinke, R.A., Lee, D.J., McDougall, B.R., King,
P.J., Victoria, J., Mao, Y., Lei, X., Reinecke, M.G., and Robinson,
W.E.,
Jr. L-chicoric acid inhibits human immunodeficiency virus type
1 (HIV-1) integration in vivo and is a non-competitive but
reversible
inhibitor of HIV-1 integrase in vitro. Virology 326:203-219
(2004).
- Olszewski, A., Sato, K., Aron, Z.D., Cohen, F., Harris, A.,
McDougall, B.R., Robinson, W.E., Jr., Overman, L.E., and
Weiss, G.A. Guanidine alkaloid analogs as inhibitors of HIV-1
Nef
interactions with p53, actin, and p56lck. Proc. Natl. Acad.
Sci., USA 101:14079-14084
(2004).
- Tanabe, H., Ouellette, A., Cocco, M.J., and Robinson,
W.E., Jr. Differential effects on human immunodeficiency
virus type 1 replication by alpha-defensins of comparable
bactericidal activities.
J. Virol. 78:11622-11631 (2004).
- Kuznetsov, Y.G., Victoria, J.G., Low, A., Robinson,
W.E., Jr., Fan, H., McPherson, A. Atomic force microscopy imaging
of retroviruses:
human immunodeficiency virus and murine leukemia virus. Scanning
26:209-216 (2004).
- Victoria, J.G. and Robinson, W.E., Jr. Disruption of the
putative splice acceptor site for SIVmac239 vif reveals tight
control
of SIV splicing and impaired replication in Vif non-permissive
cells. Virology 338:281-291 (2005).
- Lee, D.J. and Robinson, W.E., Jr. Preliminary mapping of
a putative inhibitor binding pocket for human immunodeficiency
virus type 1 integrase inhibitors. Antimicrob. Agents Chemother.
50:134-142 (2006).
- Charvat, T.T., Lee, D.J., Robinson,W.E., Jr., and Chamberlin, A.R. Design, synthesis, and biological evaluation of chicoric acid analogs as inhibitors of HIV-1 integrase. Bioorg. Med. Chem. 14:4552-4567 (2006).
- Robinson, W.E., Jr. Mechanism for complement-mediated,
antibody-dependent enhancement of human immunodeficiency virus type 1
infection in MT2 cells is enhanced entry through CD4, CD21, and CXCR4
chemokine receptors. Viral Immunol. 19:434-447 (2006).
- Peterson, M., Ke, P., Shi, H., Jones, C., McDougall, B.R., and Robinson,
W.E., Jr. Design, synthesis and antiviral evaluation of some
3'-carboxymethyl-3'-deoxyadenosine derivatives. Nucleosides, Nucleotides,
and Nucleic Acids. 26:499-519 (2007)
List of Publicatons via PubMed (NIH National Library of Medicine)
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