Administrative Appointments

  • Lead Investigator, Infectious Disease Initiative, Chan Zuckerberg Biohub (2017 - Present)
  • Institute Scholar, Stanford ChEM-H (2014 - Present)
  • Virginia & D.K. Ludwig Professor of Biochemistry, Stanford University School of Medicine (2014 - Present)
  • President, Merck Research Laboratories, Merck & Co., Inc. (2003 - 2013)
  • Executive Vice President, Merck Research Laboratories, Merck & Co., Inc. (2001 - 2002)
  • Associate Head, Department of Biology, MIT (1999 - 2001)
  • Investigator, Howard Hughes Medical Institute (1997 - 2001)
  • Professor of Biology, MIT (1995 - 2001)
  • Associate Investigator, Howard Hughes Medical Institute (1993 - 1997)
  • Member, Whitehead Institute for Biomedical Research (1992 - 2001)
  • Associate Professor of Biology, MIT (1992 - 1995)
  • Assistant Investigator, Howard Hughes Medical Institute (1990 - 1993)
  • Assistant Professor of Biology, MIT (1988 - 1992)
  • Associate Member, Whitehead Institute for Biomedical Research (1988 - 1992)
  • Whitehead Fellow, Whitehead Institute for Biomedical Research (1985 - 1988)

Honors & Awards

  • Arthur Kornberg and Paul Berg Lifetime Achievement Award in Biomedical Sciences, Stanford University (2018)
  • Member, National Academy of Sciences (1997)
  • Member, National Academy of Medicine (formerly, Institute of Medicine) (2000)
  • Member, National Academy of Engineering (2016)
  • Fellow, American Academy of Arts and Sciences (2008)
  • Doctor of Science, Honoris Causa, Pohang University of Science and Technology (2011)
  • Presidents' Circle, The National Academies (2006)
  • Harvey Lecture, The Harvey Society (2002)
  • Fellow, Biophysical Society (1999)
  • Fellow, American Association for the Advancement of Science (1999)
  • Hans Neurath Award, The Protein Society (1999)
  • Ho-Am Prize for Basic Science, The Samsung Foundation (1998)
  • Fellow, American Academy of Microbiology (1997)
  • DuPont Merck Young Investigator Award, The Protein Society (1994)
  • Eli Lilly Award in Biological Chemistry, American Chemical Society (1994)
  • NAS Award in Molecular Biology, National Academy of Sciences (1993)

Boards, Advisory Committees, Professional Organizations

  • Medical Advisory Board, Howard Hughes Medical Institute (2016 - Present)
  • Scientific Advisory Board, Vaccine Research Center, NIAID, NIH (2014 - Present)
  • MIT Corporation Visiting Committee, Department of Biology, MIT (2004 - Present)
  • Council, National Academy of Sciences (2015 - 2018)
  • Board of Scientific Advisors, Jane Coffin Childs Memorial Fund (2015 - 2018)
  • Advisory Council, Department of Molecular Biology, Princeton University (2015 - 2021)
  • External Scientific Advisory Board, Harvard Program in Therapeutic Science, HMS (2014 - 2021)

Professional Education

  • A.B., Cornell University, Chemistry (1979)
  • Ph.D., Stanford University School of Medicine, Biochemistry (1985)

Current Research and Scholarly Interests

We are studying the mechanism of viral membrane fusion and its inhibition by drugs and antibodies. We use the HIV envelope protein (gp120/gp41) as a model system. Some of our studies are aimed at creating an HIV vaccine that elicits antibodies against a transient, but vulnerable, intermediate in the membrane-fusion process, called the pre-hairpin intermediate.

We are also interested in protein surfaces that are referred to as "non-druggable". These surfaces are defined empirically based on failure to identify small, drug-like molecules that bind to them with high affinity and specificity. Some of our efforts are aimed at characterizing select non-druggable targets. We are also developing methods to identify ligands for non-druggable protein surfaces.

2023-24 Courses

Stanford Advisees

All Publications

  • Protect, modify, deprotect (PMD): A strategy for creating vaccines to elicit antibodies targeting a specific epitope PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Weidenbacher, P. A., Kim, P. S. 2019; 116 (20): 9947–52
  • Vaccination with peptide mimetics of the gp41 prehairpin fusion intermediate yields neutralizing antisera against HIV-1 isolates PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bianchi, E., Joyce, J. G., Miller, M. D., Finnefrock, A. C., Liang, X., Finotto, M., Ingallinella, P., McKenna, P., Citron, M., Ottinger, E., Hepler, R. W., Hrin, R., Nahas, D., Wu, C., Montefiori, D., Shiver, J. W., Pessi, A., Kim, P. S. 2010; 107 (23): 10655-10660


    Eliciting a broadly neutralizing polyclonal antibody response against HIV-1 remains a major challenge. One approach to vaccine development is prevention of HIV-1 entry into cells by blocking the fusion of viral and cell membranes. More specifically, our goal is to elicit neutralizing antibodies that target a transient viral entry intermediate (the prehairpin intermediate) formed by the HIV-1 gp41 protein. Because this intermediate is transient, a stable mimetic is required to elicit an immune response. Previously, a series of engineered peptides was used to select a mAb (denoted D5) that binds to the surface of the gp41 prehairpin intermediate, as demonstrated by x-ray crystallographic studies. D5 inhibits the replication of HIV-1 clinical isolates, providing proof-of-principle for this vaccine approach. Here, we describe a series of peptide mimetics of the gp41 prehairpin intermediate designed to permit a systematic analysis of the immune response generated in animals. To improve the chances of detecting weak neutralizing polyclonal responses, two strategies were employed in the initial screening: use of a neutralization-hypersensitive virus and concentration of the IgG fraction from immunized animal sera. This allowed incremental improvements through iterative cycles of design, which led to vaccine candidates capable of generating a polyclonal antibody response, detectable in unfractionated sera, that neutralize tier 1 HIV-1 and simian HIV primary isolates in vitro. Our findings serve as a starting point for the design of more potent immunogens to elicit a broadly neutralizing response against the gp41 prehairpin intermediate.

    View details for DOI 10.1073/pnas.1004261107

    View details for Web of Science ID 000278549300059

    View details for PubMedID 20483992

  • A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Miller, M. D., Geleziunas, R., Bianchi, E., Lennard, S., Hrin, R., Zhang, H. C., Lu, M. Q., An, Z. Q., Ingallinella, P., Finotto, M., Mattu, M., FINNEFROCK, A. C., Bramhill, D., Cook, J., Eckert, D. M., Hampton, R., Patel, M., Jarantow, S., Joyce, J., Ciliberto, G., Cortese, R., Lu, P., Strohl, W., Schleif, W., McElhaugh, M., Lane, S., LLOYD, C., Lowe, D., Osbourn, J., Vaughan, T., Emini, E., Barbato, G., Kim, P. S., Hazuda, D. J., Shiver, J. W., Pessi, A. 2005; 102 (41): 14759-14764


    HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a "hot spot" for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential.

    View details for DOI 10.1073/pnas.0506927102

    View details for Web of Science ID 000232603600051

    View details for PubMedID 16203977

  • Protein design of an HIV-1 entry inhibitor SCIENCE Root, M. J., Kay, M. S., Kim, P. S. 2001; 291 (5505): 884-888


    Human immunodeficiency virus type-1 (HIV-1) membrane fusion is promoted by the formation of a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 envelope glycoprotein ectodomain into close proximity. Peptides derived from the carboxyl-terminal region (called C-peptides) potently inhibit HIV-1 entry by binding to the gp41 amino-terminal region. To test the converse of this inhibitory strategy, we designed a small protein, denoted 5-Helix, that binds the C-peptide region of gp41. The 5-Helix protein displays potent (nanomolar) inhibitory activity against diverse HIV-1 variants and may serve as the basis for a new class of antiviral agents. The inhibitory activity of 5-Helix also suggests a strategy for generating an HIV-1 neutralizing antibody response that targets the carboxyl-terminal region of the gp41 ectodomain.

    View details for Web of Science ID 000166771700048

    View details for PubMedID 11229405

  • Mechanisms of viral membrane fusion and its inhibition ANNUAL REVIEW OF BIOCHEMISTRY Eckert, D. M., Kim, P. S. 2001; 70: 777-810


    Viral envelope glycoproteins promote viral infection by mediating the fusion of the viral membrane with the host-cell membrane. Structural and biochemical studies of two viral glycoproteins, influenza hemagglutinin and HIV-1 envelope protein, have led to a common model for viral entry. The fusion mechanism involves a transient conformational species that can be targeted by therapeutic strategies. This mechanism of infectivity is likely utilized by a wide variety of enveloped viruses for which similar therapeutic interventions should be possible.

    View details for Web of Science ID 000170012100023

    View details for PubMedID 11395423

  • Inhibiting HIV-1 entry: Discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket CELL Eckert, D. M., Malashkevich, V. N., Hong, L. H., Carr, P. A., Kim, P. S. 1999; 99 (1): 103-115


    The HIV-1 gp41 protein promotes viral entry by mediating the fusion of viral and cellular membranes. A prominent pocket on the surface of a central trimeric coiled coil within gp41 was previously identified as a potential target for drugs that inhibit HIV-1 entry. We designed a peptide, IQN17, which properly presents this pocket. Utilizing IQN17 and mirror-image phage display, we identified cyclic, D-peptide inhibitors of HIV-1 infection that share a sequence motif. A 1.5 A cocrystal structure of IQN17 in complex with a D-peptide, and NMR studies, show that conserved residues of these inhibitors make intimate contact with the gp41 pocket. Our studies validate the pocket per se as a target for drug development. IQN17 and these D-peptide inhibitors are likely to be useful for development and identification of a new class of orally bioavailable anti-HIV drugs.

    View details for Web of Science ID 000082981600012

    View details for PubMedID 10520998

  • HIV entry and its inhibition CELL Chan, D. C., Kim, P. S. 1998; 93 (5): 681-684

    View details for Web of Science ID 000073956700005

    View details for PubMedID 9630213

  • Influenza hemagglutinin is spring-loaded by a metastable native conformation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Carr, C. M., Chaudhry, C., Kim, P. S. 1997; 94 (26): 14306-14313


    Enveloped viruses enter cells by protein-mediated membrane fusion. For influenza virus, membrane fusion is regulated by the conformational state of the hemagglutinin (HA) protein, which switches from a native (nonfusogenic) structure to a fusion-active (fusogenic) conformation when exposed to the acidic environment of the cellular endosome. Here we demonstrate that destabilization of HA at neutral pH, with either heat or the denaturant urea, triggers a conformational change that is biochemically indistinguishable from the change triggered by low pH. In each case, the conformational change is coincident with induction of membrane-fusion activity, providing strong evidence that the fusogenic structure is formed. These results indicate that the native structure of HA is trapped in a metastable state and that the fusogenic conformation is released by destabilization of native structure. This strategy may be shared by other enveloped viruses, including those that enter the cell at neutral pH, and could have implications for understanding the membrane-fusion step of HIV infection.

    View details for Web of Science ID 000071182800018

    View details for PubMedID 9405608

  • Core structure of gp41 from the HIV envelope glycoprotein CELL Chan, D. C., Fass, D., Berger, J. M., Kim, P. S. 1997; 89 (2): 263-273


    The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of a complex of gp120 and gp41. gp120 determines viral tropism by binding to target-cell receptors, while gp41 mediates fusion between viral and cellular membranes. Previous studies identified an alpha-helical domain within gp41 composed of a trimer of two interacting peptides. The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle. Three N36 helices form an interior, parallel coiled-coil trimer, while three C34 helices pack in an oblique, antiparallel manner into highly conserved, hydrophobic grooves on the surface of this trimer. This structure shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41. Avenues for the design/discovery of small-molecule inhibitors of HIV infection are directly suggested by this structure.

    View details for Web of Science ID A1997WU88800013

    View details for PubMedID 9108481



    Influenza hemagglutinin (HA) undergoes a conformational change that induces viral fusion with the cellular membrane. The structure of HA in the fusogenic state is unknown. We have identified a sequence in HA that has a high propensity for forming a coiled coil. Surprisingly, this sequence corresponds to a loop region in the X-ray structure of native HA: the loop is followed by a three-stranded, coiled-coil stem. We find that a 36 residue peptide (LOOP-36), comprising the loop region and the first part of the stem, forms a three-stranded coiled coil. This coiled coil is extended and stabilized in a longer peptide, corresponding to LOOP-36 plus the residues of a preceding, short alpha helix. These findings lead to a model for the fusogenic conformation of HA: the coiled-coil stem of the native state extends, relocating the hydrophobic fusion peptide, by 100 A, toward the target membrane.

    View details for Web of Science ID A1993LD83000019

    View details for PubMedID 8500173