公开(公告)号：WO1991016920A1

公开(公告)日：1991-11-14

申请号：PCT/US1991002447

申请日：1991-04-10

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  HOSTETLER, Karl, Y. ,  KUMAR, Raj

IPC: A61K37/22

CPC classification number: A61K31/685 ,  A61K9/1271 ,  A61K31/66 ,  A61K47/544 ,  C07F9/10

Abstract: The present invention provides phospholipid prodrugs of aspirin, other salicylates, and nonsteroidal anti-inflammatory drugs useful in the therapy of chronic inflammatory disorders. The drugs are linked to either or both of the glycerol hydroxyls of a phospholipid or to available hydroxyls of phospholipid head groups by ester bonds. They may also be linked to available amines of phospholipid head groups by amine bonds. Drugs linked to phospholipid glycerol are released in vivo by the action of phospholipase A2 and other phospholipases, while those linked to the phospholipid head groups are released by other endogenous hydrolases. The phospholipid prodrugs reduce the gastrointestinal irritation and toxicity of these drugs when administered at high doses. The prodrugs further provide sustained serum levels of the drugs and allow longer intervals between doses through metabolically controlled release of the active agent.

Abstract translation: 本发明提供了可用于治疗慢性炎症性疾病的阿司匹林，其他水杨酸盐和非甾体抗炎药物的磷脂前药。 药物通过酯键连接到磷脂的甘油羟基中的一个或两个或通过酯键与磷脂头部的可用羟基连接。 它们也可以通过胺键与磷脂头基的有用胺连接。 与磷脂甘油连接的药物通过磷脂酶A2和其他磷脂酶的作用在体内释放，而与磷脂头基团连接的药物则被其他内源水解酶释放。 当以高剂量施用时，磷脂前药降低了这些药物的胃肠道刺激和毒性。 前药进一步提供药物的持续血清水平并且通过代谢控制释放活性剂允许剂量之间更长的间隔。

公开(公告)号：WO1993001828A1

公开(公告)日：1993-02-04

申请号：PCT/US1992006153

申请日：1992-07-22

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  BASAVA, Channa ,  HOSTETLER, Karl, Y.

IPC: A61K37/02

CPC classification number: C07K14/005 ,  A61K38/00 ,  C07C69/96 ,  C07F9/10 ,  C07K1/006 ,  C07K1/1075 ,  C07K1/1077 ,  C07K5/0202 ,  C07K5/0205 ,  C07K5/06052 ,  C07K5/06069 ,  C07K5/06095 ,  C07K5/06113 ,  C07K5/06191 ,  C07K5/081 ,  C07K5/0823 ,  C07K5/1008 ,  C07K5/1016 ,  C07K11/00 ,  C12N2740/16222

Abstract: Compounds wherein therapeutic peptides, including HIV protease inhibitors, are covalently linked to phospholipids, glycerides or other membrane-targeting and membrane-anchoring species, and their pharmaceutically acceptable salts, together with processes for their preparation. The invention also provides novel HIV protease inhibitors. The compounds of the present invention possess useful pharmacological properties such as antiviral activity towards viral infection and inhibitory activity towards viral proteases. Therefore, theses compounds can be used in the prophylaxis or treatment of viral infections, in particular infections caused by HIV and other retroviruses. The targeting technology as described for the protease inhibitors is also applicable to a variety of inhibitors of other enzymes.

Abstract translation: 包含HIV蛋白酶抑制剂的治疗性肽与磷脂，甘油酯或其它膜靶向和膜锚定物质以及它们的药学上可接受的盐共同连接的化合物及其制备方法。 本发明还提供了新的HIV蛋白酶抑制剂。 本发明的化合物具有有效的药理学性质，例如对病毒感染的抗病毒活性和对病毒蛋白酶的抑制活性。 因此，这些化合物可用于预防或治疗病毒感染，特别是HIV和其他逆转录病毒引起的感染。 针对蛋白酶抑制剂所述的靶向技术也适用于各种其它酶的抑制剂。

公开(公告)号：WO1992021369A1

公开(公告)日：1992-12-10

申请号：PCT/US1992004854

申请日：1992-06-03

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  BASAVA, Channa ,  HOSTETLER, Karl, Y.

IPC: A61K37/02

CPC classification number: C07K14/585 ,  A61K38/00

Abstract: Synthetic hypocalcemic peptides which are superior in biological properties to native calcitonins as clinically useful agents. The peptides comprise analogues of native calcitonins having amino acid additions at the N-terminal position which, either alone or together with substitutions, and deletions at other residues, act to improve potency, prolong duration of the hormonal effect, and increase oral or nasal bioavailability. Methods are provided for the synthesis of these peptides.

Abstract translation: 生物学性质优于天然降钙素的合成低钙肽作为临床有用的药剂。 肽包括在N-末端位置具有氨基酸添加的类似物，其单独地或与取代一起，以及在其它残基处的缺失，用于提高效力，延长激素效应的持续时间，以及增加口服或鼻部生物利用度 。 提供了用于合成这些肽的方法。

公开(公告)号：WO1991007978A1

公开(公告)日：1991-06-13

申请号：PCT/US1990006352

申请日：1990-10-31

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  BASAVA, Channa ,  HOSTETLER, Karl, Y.

IPC: A61K37/02

CPC classification number: C07K14/585 ,  A61K38/00

Abstract: Synthetic hypocalcemic peptides which are similar in biological properties to native calcitonins as clinically useful agents. The peptides comprise analogues of native calcitonins having amino acid substitutions and deletions which act to improve potency, prolong duration of the hormonal effect, enhance receptor binding, and increase oral or nasal bioavailability. The calcitonin peptide analogues are less expensive and more easily synthesized than native calcitonins, and have improved resistance to inactivation or degradation. Methods are provided for the synthesis of these peptides. Also disclosed are novel cyclic peptides, including calcitonin, having increased stability with respect to proteolysis. Methods for the synthesis of these peptides are provided, comprising converting disulfide cyclic peptides and proteins to enzymatically and chemically stable cyclic peptide structures by the replacement of cysteine residues with dicarboxylic acids and diamino acids. The method is applicable to various naturally occurring peptides, their synthetic analogues or derivatives, and proteins.

公开(公告)号：WO1993014778A1

公开(公告)日：1993-08-05

申请号：PCT/US1993000492

申请日：1993-01-21

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  RHODES, Gary, H. ,  DWARKI, Varavani, J. ,  FELGNER, Philip, L. ,  HWANG-FELGNER, Jiin-Yu ,  MANTHORPE, Marston

IPC: A61K37/00

CPC classification number: A61K38/57 ,  A61K9/1272 ,  A61K35/12 ,  A61K38/00 ,  A61K38/185 ,  A61K39/0003 ,  A61K39/12 ,  A61K39/21 ,  A61K48/00 ,  A61K2039/5156 ,  A61K2039/53 ,  A61K2039/55555 ,  C07K14/48 ,  C12N2740/16134

Abstract: A method for delivering a polypeptide to the interior of a cell of a vertebrate ex vivo is provided comprising the steps of: removing live cells from the vertebrate, contacting the cells with a preparation comprising an effective amount of polynucleotide operatively coding for the polypeptide and lipid effective to deliver the polynucleotide in the cells; and freezing or returning the cells to the vertebrate within 48 hours after the contacting step so that the cells express the polynucleotide in vivo. The method additionally can comprise substantially separating the cells from the surrounding extracellular matrix.

Abstract translation: 提供了一种将多肽递送到离体脊椎动物细胞内部的方法，包括以下步骤：从脊椎动物中除去活细胞，使细胞与包含有效量的可操作地编码多肽和脂质的多核苷酸的制剂接触 有效地将细胞中的多核苷酸递送; 并且在接触步骤后48小时内将细胞冷冻或返回到脊椎动物，使得细胞在体内表达多核苷酸。 该方法另外可以包括基本上将细胞与周围细胞外基质分离。

公开(公告)号：WO1991017424A1

公开(公告)日：1991-11-14

申请号：PCT/US1991002962

申请日：1991-04-29

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  FELGNER, Philip, L.

IPC: G01N21/00

CPC classification number: A61K9/1271 ,  A61K9/1272

Abstract: Disclosed are methods and compositions for facilitating intracellular delivery of biologically active substances of pharmaceutical agents, comprising self-assembling complexes of positively and negatively charged lipid species capable of interacting with a substance to be delivered. The assembled complexes have a net positive charge suitable for spontaneously attaching to negatively charged cell membranes, and may comprise a neutral or positively charged bioactive substance first encapsulated in or complexed with negatively charged lipid vesicles which are next complexed with cationic lipid vesicles having a net positive charge before or in the process of administration to the cell.

Abstract translation: 公开了用于促进药物的生物活性物质的细胞内递送的方法和组合物，包括能够与待递送物质相互作用的带正电荷和带负电荷的脂质物质的自组装复合物。 组装的复合物具有适合于自发附着到带负电荷的细胞膜的净正电荷，并且可以包含首先包封在带负电荷的脂质囊泡中或与带负电荷的脂质囊泡络合的中性或带正电荷的生物活性物质，其随后与具有净阳性的阳离子脂质囊泡复合 在给予细胞前或给药过程中进行电荷注射。

公开(公告)号：WO1991016024A1

公开(公告)日：1991-10-31

申请号：PCT/US1991002691

申请日：1991-04-18

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  FELGNER, Philip, L. ,  KUMAR, Raj ,  BASAVA, Channa ,  BORDER, Richard, C. ,  HWANG-FELGNER, Jiin-Yu

IPC: A61F13/00

CPC classification number: C12N15/88 ,  A61K9/0014 ,  A61K9/0019 ,  A61K9/1272 ,  A61K47/186 ,  A61K47/54 ,  A61K47/544 ,  A61K47/645

Abstract: Disclosed are cationic lipids capable of facilitating transport of biologically active agents into cells, including the transfection of cells by therapeutic polynucleotides, the delivery of antiviral drugs, and the introduction of immunogenic peptides. The cationic lipids, comprising an ammonium group, have general structure (I). Also disclosed are adducts of these compounds comprising additional cationic sites that enhance the transfective or transport activity. Structure-activity correlations provide for the selection of preferred compounds to be synthesized for this purpose. Compositions disclosed for use of these cationic lipids include formulations for in vitro transfection and pharmaceutical formulations for parenteral and topical administration of therapeutic agents.

公开(公告)号：WO1990000555A1

公开(公告)日：1990-01-25

申请号：PCT/US1989002909

申请日：1989-06-30

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  HOSTETLER, Karl, Y. ,  KUMAR, Raj ,  STUHMILLER, Louise, M.

IPC: C07H15/12

CPC classification number: C07H15/04 ,  A01N43/40 ,  A61K9/127 ,  A61K47/542 ,  A61K47/544 ,  A61K47/548 ,  C07C17/093 ,  C07C25/13 ,  C07D213/61 ,  C07D213/64 ,  C07D213/70 ,  C07H19/04 ,  C07H19/06 ,  C07H19/16

Abstract: Compounds are disclosed for treating AIDS, herpes, and other viral infections by means of lipid derivatives of antiviral agents. The compounds consist of nucleoside analogues having antiviral activity which are linked, commonly through a phosphate group at the 5' position of the pentose residue, to one of a selected group of lipids. The lipophilic nature of these compounds provide advantages over the use of the nucleoside analogue alone. It also makes it possible to incorporate them into the lamellar structure of liposomes, either alone or combined with similar molecules. In the form of liposomes, these antiviral agents are preferentially taken up by macrophages and monocytes, cells which have been found to harbor the target HIV virus. Additional site specificity may be incorporated into the liposomes with the addition of ligands, such as monoclonal antibodies or other peptides of proteins which bind to viral proteins. Effective nucleoside analogues are dideoxynucleosides, azidothymine (AZT), and acyclovir; lipid groups may be glycolipids, sphingolipids, phospolipids or fatty acids. The compounds persist, after intracellular hydrolysis, as phosphorylated or non-phosphorylated antiviral nucleosides. The compounds are effective in improving the efficacy of antiviral nucleoside analogues by prolonging the antiviral activity after the administration of the drug has ended, and in preventing retroviral replication in HIV infections which have become resistant to therapy with conventional forms of the antiretroviral agents.

公开(公告)号：WO1997047197A1

公开(公告)日：1997-12-18

申请号：PCT/US1997009439

申请日：1997-06-03

Applicant: PASTEUR MERIEUX SERUMS ET VACCINS ,  VICAL, INC. ,  TEXAS HEALTH SCIENCE CENTER, UNIVERSITY OF, AT SAN ANTONIO

Inventor： PASTEUR MERIEUX SERUMS ET VACCINS ,  VICAL, INC. ,  TEXAS HEALTH SCIENCE CENTER, UNIVERSITY OF, AT SAN ANTONIO ,  HUEBNER, Robert, C. ,  NORMAN, Jon, A. ,  LIANG, Xiaowu ,  CARNER, Kristin, R. ,  BARBOUR, Alan, G. ,  LUKE, Catherine, J.

IPC: A01N43/04

CPC classification number: C07K14/20 ,  A61K39/00 ,  C12N15/85 ,  Y02A50/401 ,  Y10S977/804

Abstract: Plasmid DNA encoding at least one Borrelia genospecies antigen and methods for making and using such a plasmid are disclosed and claimed. The genospecies can be burgdorferi, garinii and/or afzelli. The antigen can be OspA and/or OspB and/or OspC. Compositions containing the plasmid DNA are useful for administration to a host susceptible to Lyme Disease for an in vivo response, such as a protective response, or for generating useful antibodies. The inventive plasmid can also be transfected into cells for generating antigens in vitro. And, the inventive plasmid can be prepared by isolating DNA (such as DNA coding for: promoter, leader sequence, antigen, and terminator) and performing a ligation or ligations, such as a three-way ligation. More particularly, administration of DNA encoding Borrelia genospecies antigen, e.g., OspA and/or OspB and/or OspC and compositions therefor for eliciting an immunological response against Borrelia, such as a protective response preventive of Lyme Disease, are disclosed and claimed. Thus, Lyme Disease vaccines or immunological compositions, and methods of making and using them, are disclosed and claimed.

Abstract translation: 公开并要求保护编码至少一种疏螺旋体基因种抗原的质粒DNA和制备和使用这种质粒的方法。 基因型可以是布尔加斯多，加里尼和/或阿兹齐利。 抗原可以是OspA和/或OspB和/或OspC。 含有质粒DNA的组合物可用于施用对莱姆病敏感的宿主体内应答，例如保护性反应或产生有用的抗体。 本发明的质粒也可以转染入体外产生抗原的细胞中。 并且，本发明的质粒可以通过分离DNA（例如编码：启动子，前导序列，抗原和终止子的DNA）并进行连接或连接，例如三向连接来制备。 更具体地，公开和要求保护编码疏螺旋体属基因种抗原的DNA，例如OspA和/或OspB和/或OspC及其组合物，用于引发对Borrelia的免疫应答，例如预防莱姆病的保护性应答。 因此，公开和要求保护莱姆病疫苗或免疫组合物，以及制造和使用它们的方法。

公开(公告)号：WO1993003709A1

公开(公告)日：1993-03-04

申请号：PCT/US1992004225

申请日：1992-05-19

Applicant: VICAL, INC.

Inventor： VICAL, INC. ,  FELGNER, Philip, L. ,  ABAI, Anna, M. ,  MANTHORPE, Marston, C.

IPC: A61K09/127

CPC classification number: C07K14/4712 ,  A61K9/1271 ,  A61K9/1272 ,  A61K38/465 ,  A61K47/543 ,  A61K48/00 ,  C12Y301/21001 ,  A61K2300/00

Abstract: Disclosed is a pharmaceutical composition suitable for the pulmonary administration of therapeutically effective amounts of DNase, a macromolecule operatively coding for a functional protein to remedy the cellular defect associated with cystic fibrosis and sufficient lipid to form cationic complexes with the macromolecule, effective to deliver the macromolecule into pulmonary cells in vivo. Additionally disclosed are methods for the treatment of cystic fibrosis.

Abstract translation: 公开了适用于肺部给予治疗有效量的DNA酶的药物组合物，其是可操作地编码功能性蛋白质的大分子，用于补救与囊性纤维化相关的细胞缺陷和足够的脂质与大分子形成阳离子配合物，有效递送大分子 在体内进入肺细胞。 另外公开了治疗囊性纤维化的方法。