Combretastatin A4 is a stilbenoid tubulin binding mitotic inhibitor whose conformation greatly influences its potency, making it an excellent candidate for adaptation as a photoactivatable tool. Herein we report a novel synthesis, the facile isomerization with commercial grade equipment, and biological activity of azo-combretastatin A4 in vitro and in human cancer cells. Photoisomerized azo-combretestatin A4 is at least 200-fold more potent in cellular culture, making it a promising phototherapeutic and biomedical research tool.

SUMMARY New World hantaviruses (NWHs) are endemic in North and South America and cause hantavirus cardiopulmonary syndrome (HCPS), with a case fatality rate of up to 40%. Knowledge of the natural humoral immune response to NWH infection is limited. Here, we describe human monoclonal antibodies (mAbs) isolated from individuals previously infected with Sin Nombre virus (SNV) or Andes virus (ANDV). Most SNV-reactive antibodies show broad recognition and cross-neutralization of both New and Old World hantaviruses, while many ANDV-reactive antibodies show activity for ANDV only. mAbs ANDV-44 and SNV-53 compete for binding to a distinct site on the ANDV surface glycoprotein and show potently neutralizing activity to New and Old World hantaviruses. Four mAbs show therapeutic efficacy at clinically relevant doses in hamsters. These studies reveal a convergent and potently neutralizing human antibody response to NWHs and suggest therapeutic potential for human mAbs against HCPS.

Hantaviruses are zoonotic pathogens found in parts of Europe, Asia, South America, and North America, which can cause renal and respiratory failure with fatality rates up to 40%. There are currently no FDA-approved vaccines or therapeutics for hantavirus-related diseases; however, it is evident that a robust neutralizing antibody response is critical for protection from severe disease. Although virologists first described this family of viruses in the 1950s, there is limited information on the neutralizing epitopes that exist on the hantavirus antigenic glycoproteins, Gn and Gc, and sites important for the design of effective therapeutics and vaccines. We provide a thorough summary of the hantavirus field from an immunological perspective. In particular, we discuss our current structural knowledge of antigenic proteins Gn and Gc, identification of B cell neutralizing epitopes, previously isolated monoclonal antibodies and their cross-reactivity between different hantavirus strains, and current developments toward vaccines and therapeutics. We conclude with some outstanding questions in the field and emphasize the need for additional studies of the human antibody response to hantavirus infection. IMPORTANCE Hantaviruses are pathogens that sometimes pass from animals to humans, and they are found in parts of Europe, Asia, and North and South America. When human infection occurs, these viruses can cause kidney or lung failure, and as many as 40% of infected people die. Currently, there are no vaccines or therapeutics for hantavirus-related diseases available. A first step in developing prevention measures is determining what type of immune response is protective. Increasingly it has become clear that the induction of a type of response called a neutralizing antibody response is critical for protection from severe disease. Although virologists first described this family of viruses in the 1950s, there is limited information on what features on the surface of hantaviruses are recognized by the immune system. Here, we review the current state of knowledge of this information, which is critical for the design of effective therapeutics and vaccines.

Hantaviruses are high-priority emerging pathogens carried by rodents and transmitted to humans by aerosolized excreta or, in rare cases, person-to-person contact. While infections in humans are relatively rare, mortality rates range from 1 to 40% depending on the hantavirus species. There are currently no FDA-approved vaccines or therapeutics for hantaviruses, and the only treatment for infection is supportive care for respiratory or kidney failure. Additionally, the human humoral immune response to hantavirus infection is incompletely understood, especially the location of major antigenic sites on the viral glycoproteins and conserved neutralizing epitopes. Here, we report antigenic mapping and functional characterization for four neutralizing hantavirus antibodies. The broadly neutralizing antibody SNV-53 targets an interface between Gn/Gc, neutralizes through fusion inhibition and cross-protects against the Old World hantavirus species Hantaan virus when administered pre- or post-exposure. Another broad antibody, SNV-24, also neutralizes through fusion inhibition but targets domain I of Gc and demonstrates weak neutralizing activity to authentic hantaviruses. ANDV-specific, neutralizing antibodies (ANDV-5 and ANDV-34) neutralize through attachment blocking and protect against hantavirus cardiopulmonary syndrome (HCPS) in animals but target two different antigenic faces on the head domain of Gn. Determining the antigenic sites for neutralizing antibodies will contribute to further therapeutic development for hantavirus-related diseases and inform the design of new broadly protective hantavirus vaccines.

Therapeutic antibodies against flaviviruses often promote neutralization by targeting the envelope protein of the virion. However, this approach is hindered by a possible concern for antibody-dependent enhancement of infection and paradoxical worsening of disease.