polypeptide comprising at least eight contiguous amino acids; have antiviral activity; human immunodeficiency virus (mV), e.g., HIV-1 or HIV-2, or influenza virus
Inventors
Boyd, Michael R. • Mori, Toshiyuki • O'Keefe, Barry R.
Assignees
US Department of Health and Human Services
Publication Number
US-7884178-B2
Publication Date
2011-02-08
Expiration Date
2025-05-27
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Abstract
An isolated and purified nucleic acid molecule that encodes a polypeptide comprising at least eight contiguous amino acids of SEQ ID NO: 3, wherein the at least eight contiguous amino acids have anti-viral activity, as well as an isolated and purified nucleic acid molecule that encodes a polypeptide comprising at least eight contiguous amino acids of SEQ ID NO: 3, wherein the at least eight contiguous amino acids have anti-viral activity, and, when the at least eight contiguous amino acids comprise amino acids 1-121 of SEQ ID NO: 3, the at least eight contiguous amino acids have been rendered glycosylation-resistant, a vector comprising such an isolated and purified nucleic acid molecule, a host cell comprising the nucleic acid molecule, optionally in the form of a vector, a method of producing an anti-viral polypeptide or conjugate thereof, the anti-viral polypeptide itself, a conjugate or fusion protein comprising the anti-viral polypeptide, and compositions comprising an effective amount of the anti-viral polypeptide or conjugate or fusion protein thereof. Further provided are methods of inhibiting prophylactically or therapeutically a viral infection of a host.
Core Innovation
The invention provides an isolated and purified anti-viral polypeptide derived from Griffithsia sp., referred to as griffithsin, comprising at least eight contiguous amino acids of SEQ ID NO: 3 that have antiviral activity. This polypeptide binds to viruses, particularly retroviruses such as HIV-1, HIV-2, SIV, and influenza viruses, by targeting high mannose-containing oligosaccharide constituents of viral envelope glycoproteins, thereby inhibiting viral binding, fusion, and entry.
The invention also provides nucleic acid molecules encoding griffithsin or glycosylation-resistant variants, vectors comprising these nucleic acids, host cells transformed to express griffithsin, and methods of producing griffithsin in recombinant systems. Furthermore, it includes griffithsin conjugates and fusion proteins where griffithsin is coupled to effector components such as toxins, immunological reagents, antiviral agents, or solid supports.
The methods encompass prophylactic and therapeutic inhibition of viral infections in hosts by administering effective amounts of griffithsin or its conjugates. Additional strategies include the use of engineered commensal microorganisms expressing griffithsin at mucosal sites, compositions comprising griffithsin attached to solid supports for viral removal from biological samples, and the induction of immune responses via anti-griffithsin antibodies or anti-idiotypic antibodies with internal images of viral glycoproteins.
Claims Coverage
The patent includes two independent claims focusing on the anti-viral polypeptide and its glycosylation-resistant variants, along with their compositions and carriers. The main inventive features are extracted as follows.
Anti-viral polypeptide with glycosylation-resistant modifications
An isolated anti-viral polypeptide comprising SEQ ID NO: 3 or a variant thereof wherein one or more amino acid residues at positions 45, 60, 71, or 104 have been rendered glycosylation-resistant, and the polypeptide retains anti-viral activity.
Isolated anti-viral polypeptide comprising SEQ ID NO: 3
An isolated anti-viral polypeptide comprising the amino acid sequence of SEQ ID NO: 3 with inherent anti-viral activity.
The independent claims cover isolated anti-viral polypeptides of SEQ ID NO: 3, including variants with glycosylation-resistant substitutions, and compositions comprising these polypeptides in carriers. These inventive features relate to the structure and functional modifications affecting glycosylation, maintaining antiviral activity.
Stated Advantages
Anti-viral polypeptides exhibit potent inactivation of diverse HIV strains and influenza viruses at low nanomolar to picomolar concentrations without cytotoxicity to target cells.
Griffithsin and its conjugates bind specifically to viral envelope glycoproteins, efficiently inhibiting virus-cell binding, fusion, and entry, with broad-spectrum antiviral activity.
The polypeptides are resistant to degradation, can be produced recombinantly at high yield, and can be modified or fused to effector molecules to enhance therapeutic efficacy and delivery.
Documented Applications
Prophylactic and therapeutic treatment of viral infections caused by retroviruses such as HIV-1, HIV-2, SIV, and influenza viruses in humans and animals.
Topical microbicides to prevent sexual transmission of HIV via mucosal application to genital, rectal, oral, or penile sites.
Use of engineered commensal microorganisms, such as lactobacilli, expressing griffithsin for sustained in vivo antiviral protection at mucosal sites.
Compositions comprising griffithsin attached to solid support matrices (e.g., magnetic beads or contraceptive devices) for ex vivo removal or inactivation of infectious viruses in biological fluids such as blood, sperm, cells, tissues, or organs.
Induction of immune responses by administering griffithsin or anti-griffithsin antibodies, including anti-idiotypic antibodies that mimic viral glycoproteins, to stimulate antiviral immunity.
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