Pharmaceutical applications Editorial overview

Viruses rule O.K.

Tim Harris

Glaxo Group Research Ltd, Greenford, UK

Current Opinion in Biotechnology 1992, 3:641-642

Viruses have had a large impact in biotechnology and the pharmaceutical industry. Not only is there consid- erable interest in finding new chemical entities to in- hibit viruses causing important diseases, such as AIDS, chicken pox (shingles) and influenza, but viruses and virus nucleic acids are being used as vectors or in vector constructs and in various expression systems (e.g. vaccinia and baculovirus). In addition, it is be- coming increasingly obvious that viruses, particularly those with large genomes, harbor genes, the expres- sion of which is designed to limit the response of the host to infection [1].

At first sight, the collection of reviews in this section might be considered diverse and distinct. Viruses are, however, a recurring theme. The reviews have been organized to go (like hunting the thimble) from hot (very virological) to cold (little to do with viruses). In the first one, Christopher Hellen and Eckard Wim- mer (pp 643-649) discuss viral proteases as therapeutic targets. They concentrate on the picomavirus cysteine (serine) proteinases and the aspartyl proteinase in HIV and other retroviruses. These enzymes are the means by which the polyproteins coded for by the virus RNA are matured in-to capsid proteins. It is now apparent that other virus families (e.g. the herpes viruses) also encode enzymes involved in virus assembly. These proteins will be of continuing interest to the industry as points of intervention in controlling the infections. A great deal of effort has been spent trying to find orally bioavailable and efficacious inhibitors of HIV protease without success. Perhaps another approach is needed. Studies of the immunopathology of AIDS may identify other ways to control the disease. An- gus Dalgleish (pp 650-655) elegantly reviews potential immunotherapeutic approaches to modification of this disease, including vaccination.

The fact that the full sequence of several virus genomes have been elucidated in recent years makes virus in- fections an obvious target for oligonucleotide-based therapy. The review by Stanley Crooke (pp656-661) concentrates on some of the novel chemistry (e.g. pep- tide nucleic acids) now being employed in this area and some of the mechanisms by which short nucleic acid derivatives exert their effect. The pharmacoki- netic profile of this class of drug moelcule is often ignored or underestimated and it is useful to have

the basic conclusions of the studies that have been done documented here. It seems to me quite likely that the current pharmacopeia will be supplemented with antisense drugs targeted towards particular virus infections, such as human papilloma virus or herpes keratitis.

Viruses are very good at 'hijacking' cellular activities for their own ends. Members of the immunoglobulin superfamily of adhesion molecules such as intercellular adhesion molecule ICAM-1 and CD4 have turned out to be virus receptors for rhinovirus and HIV, respectively. Martyn Robinson and Paul Stephens (pp 662-667) have restricted their review on cellular adhesion molecules to the interaction occurring between neutrophils and endothelial cells. This is probably just as well, given the fast moving and complicated nature of the field. The dynamics of the process of cellular adhesion can- not be overstressed and the need for models accurately reflecting what is happening i n v i vo is paramount. Monoclonal antibodies directed to various adhesion molecules are helping to unravel the roles of differ- ent proteins and the conceptually simple 'roiling and sticking' model is proving to be useful. The initial inter- action between neutrophii and endothelial cell surface is mediated by selectins followed by a more firm at- tachment via CD18 integrins. Monoclonal antibodies such as anti-ICAM-1 have been tested clinically and may be effective. The molecular understanding of the various protein-protein or protein-carbohydrate inter- actions and the conformational changes occuring in different proteins on activation suggest, however, that there is plenty of opportunity to find small molecule in- hibitors of different elements of the adhesion process. Integrin-modulating factor may be but the tip of a big iceberg.

Herman Waldmann and colleagues (pp668-674) in their review of immunosuppression also cover the use of monoclonal antibodies as therapeutics, in particular those that are targeted to T cells and antigen-presenting cells. As the authors state, it is difficult to correlate ani- mal data obtained with many antibodies to what might occur in humans but there are encouraging signs that tolerance might be induced. The virus theme remerges in this review too, as the utilization of interleukin-lc~ receptor antagonist in modulating the effects of T cells may be a direct mimick of the way viruses inhibit T

© Current Biology Ltd ISSN 0958-1669 641

642 Editorial overview

cell inactivation by synthesizing interleukin-1 binding proteins and related molecules [2,3].

The link between twelve transmembrane domain pro- teins and viruses may appear rather more tenuous than the above. However, it turns out that one of these proteins, which is a receptor for an ecotropic mouse retrovirus, corresponds to a previously char- acterised cationic L-amino-acid transporter. As more virus genomes are sequenced it would not surprise me if twelve transmembrane domain proteins were revealed. After all, members of the herpesvirus family code for seven transmembrane receptor homologues, the ligands for which, like many other such 'orphan' receptors are not yet know. The review by John Kilty and Susan Amara (pp 6754582) considers members of the twelve transmembrane domain family including the sugar transporters, the multiple drug resistance P glycoprotein, the cystic fibrosis transmembrane-con- ductance regulator and transporters for various nu- cleosides. The re-uptake of neurotransmitters (such as dopamine and serotonin) which play an important role in synaptic transmission, is also mediated by members of this protein family. Several important drugs affecting these receptors are already in existence (e.g. the sero- tonin re-uptake inhibitors used to treat depression), so structure-function studies similar to those undertaken for the seven transmembrane receptors will be of par- ticular interest. The pharmacology of the twelve trans- membrane family is usefully brought together in Table 1 (pp 678).

An attempt to link viruses to Alzheimer's disease would stretch the common theme too far but Chris Miller and Brian Anderton's review (pp 6834586) of transgenic an- imal models of Alzheimer's disease would not have re- ally been possible without the use of viruses. Pieces of viral genomes in the form of promoters and other gene expression control elements are important parts of vec- tor technology, which is a key component of transge- nesis. This review is rather timely given the problems that have been encountered in trying to obtain repro- ducible Alzheimer's disease-like pathology in murine brain, starting with the ~-amyloid gene under the con- trol of various promoters. The authors suggest that the construction of transgenic lines with mutant amyloid precursor protein genes designed to be processed in

particular ways may be the way forward. Of course, as with other transgenic neurological models, larger rodents provide a more robust test system and trans- genic rats may be useful.

The final review of the section also has virological overtones. This time as a direct and specific ther- apy (granulocyte colony-stimulating factor for AIDS neutropaenia). The colony-stimulating factors are a paradigm for biotechnologically driven therapy. The function of the molecules was only understood as a direct consequence of their cloning and expres- sion: the clinical testing followed as a consequence. Michael Dexter and Nydia Testa (pp 687-692) take us through the licensed products, erythropoietin, gran- ulocyte colony-stimulating factor and granutocyte- macrophage colony-stimulating factor, as well as those like interleukin-3 and stem cell factor currently under- going clinical testing. The ability to stimulate stem cells e x v i v o for bone marrow transplantations and the non- haematopoietic effects of the factors will be important.

As someone who was fortunate enough to work with viruses at a molecular level for several years before cloning (b.c.) it is good to be able to find a famil- iar and enduring theme in this collection of reviews for "Pharmaceutical applications" of biotechnology. I hope readers of the articles derive as much from them as I have.

References

GOODING LR: Vi rus P r o t e i n s t h a t C o u n t e r a c t H o s t Im- m u n e Defenses . Cell ]992, 71:5-7,

SPRIGGS MK, HORBY DL, MALISZEUSKI CR, PICKUP DJ, BULLER RML, VANSLYKE J: Vacc in ia a n d C o w p o x V i ru se s E n c o d e a N o v e l Secreted I n t e r l euk in -1 B i n d i n g P r o t e i n . Cell 1992, 71:145-152.

ALCAMI A, SMITH GL: A Soluble R e c e p t o r for I n t e r l e u k i n - 1~ E n c o d e d b y Vacc in ia Virus: a Nove l M e c h a n i s m o f M o d u l a t i o n o f t h e Host R e s p o n s e to In fec t i on . Cell 1992, 71:153-167.

TJR Harris, Director of Biotechnology, Glaxo Group Research Ltd, Greenford Road, Greenford, Middlesex UB6 0HE, UK.