Nucleotides as Herpesvirus-Specific Inhibitors of

Chapter 8

Nucleotides as Herpesvirus-Specific Inhibitors of Protein Glycosylation Roelf Datema and Sigvard Olofsson 1

2

Bristol-Myers Company, Pharmaceutical Research and Development Division, 5 Research Parkway, Wallingford, CT 06492-7660 Göteborgs Universitet, Department of Clinical Virology, Guldhedsgatan 10B, S-41346 Göteborg, Sweden

Downloaded by UNIV LAVAL on May 13, 2016 | http://pubs.acs.org Publication Date: August 22, 1989 | doi: 10.1021/bk-1989-0401.ch008

1

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We describe a strategy to obtain herpesvirus-specific glycosylation inhibitors. This involves selective phosphorylation in infected cells of a nucleoside analog to a 5'-monophosphate, which inhibits translocation of sugar nucleotides from the cytoplasm into the Golgi-compartment where the terminal glycosyltransferases are located. Such an inhibitor may be useful in antiviral chemotherapy, or could serve as a tool to study the role of terminal glycosylation of viral glycoproteins in the intact host organism. V i r a l p r o t e i n s a r e N - g l y c o s y l a t e d i n i t i a l l y by t h e t r a n s f e r en b l o c o f a g l u c o s y l a t e d high-mannose t y p e o l i g o s a c c h a r i d e f r o m t h e l i p i d d o l i c h o l - d i p h o s p h a t e u s u a l l y t o a n a s c e n t p r o t e i n (1). T r a n s f e r o f n o n - g l u c o s y l a t e d o l i g o s a c c h a r i d e s has been o b s e r v e d ( 2 ) , b u t , as y e t , n o t w i t h v i r a l p r o t e i n s . The N - l i n k e d o l i g o s a c c h a r i d e s a r e p r o c e s s e d by g l y c o s i d a s e s , and some o f t h i s p r o c e s s i n g o c c u r s i n t h e rough e n d o p l a s m i c r e t i c u l u m ( 3 ) . The e x t e n t o f p r o c e s s i n g i s dependent on a v a r i e t y o f c o n d i t i o n s , which may i n c l u d e t h e l o c a t i o n o f a p a r t i c u l a r o l i g o s a c c h a r i d e on the p r o t e i n ( 4 ) , b u t t h e removal o f g l u c o s e r e s i d u e s a p p e a r s t o be u b i q u i t o u s . The t r i m m i n g o f s u g a r r e s i d u e s and t h e subsequent a d d i t i o n o f p e r i p h e r a l sugars, t o r e s u l t i n s o - c a l l e d hybrid-type o r complex-type o l i g o s a c c h a r i d e s , o c c u r s by c o n c e r t e d a c t i o n o f g l y c o s i d a s e s and g l y c o s y l t r a n s f e r a s e s i n t h e G o l g i a p p a r a t u s ( 9 ) , and c a n r e s u l t i n a p l e t h o r a o f o l i g o s a c c h a r i d e s . (See F i g u r e 1 f o r one example.) Some v i r a l g l y c o p r o t e i n s c o n t a i n 0 - l i n k e d o l i g o s a c c h a r i d e s , u s u a l l y i n a d d i t i o n t o N - l i n k e d o l i g o s a c c h a r i d e s ( 5 ) . The 0 - l i n k e d o l i g o s a c c h a r i d e s a r e assembled by s t e p w i s e a d d i t i o n o f sugar r e s i d u e s o n t o a p r o t e i n i n t r a n s i t t h r o u g h t h e G o l g i a p p a r a t u s ( 6 ) . Thus, t h e s y n t h e s i s o f 0 - l i n k e d o l i g o s a c c h a r i d e s occurs simultaneously with the a d d i t i o n o f p e r i p h e r a l sugars t o 0097-45156/89/0401-0116S06.00/0 o 1989 A m e r i c a n C h e m i c a l Society

Martin; Nucleotide Analogues as Antiviral Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

8.

DATEMA AND OLOFSSON

Inhibitors of Protein Glycosylation

N - l i n k e d o l i g o s a c c h a r i d e s , and t h e s e p r o c e s s e s "terminal glYCOsylation" (7).

a r e r e f e r r e d t o as


The b i o l o g i c a l r o l e o f t e r m i n a l g l y c o s y l a t i o n o f v i r a l glycoproteins S e v e r a l l o w - m o l e c u l a r w e i g h t compounds ( s u g a r a n a l o g s and a l k a l o i d s ) a r e known t o i n h i b i t d i s c r e t e s t e p s o f t h e t r i m m i n g pathway, as shown i n F i g u r e 1, and have been u s e d t o s t u d y t h e b i o l o g i c a l r o l e o f the o l i g o s a c c h a r i d e processing using v i r u s - i n f e c t e d c e l l s i n c u l t u r e . I t became r a p i d l y a p p a r e n t t h a t t h e b i o l o g i c a l e f f e c t s were s t r o n g l y dependent on t h e p a r t i c u l a r p r o t e i n o r v i r a l system ( 8 ) . Examples i n c a s e a r e two r e t r o v i r a l systems. I n b o t h Rous Sarcoma V i r u s (RSV)- and murine l e u k e m i a v i r u s (MuLV)-infected c e l l s , b l o c k i n g N - g l y c o s y l a t i o n i n t e r f e r e s with c o r r e c t p r o t e o l y t i c p r o c e s s i n g o f the envelope g l y c o p r o t e i n s t o s t a b l e e n d - p r o d u c t s and t h e i n c o r p o r a t i o n o f t h e s e p r o t e i n s i n t o v i r i o n s (9-10). Allowing N-glycosylation but blocking o l i g o s a c c h a r i d e t r i m m i n g by any o f t h e g l u c o s i d a s e i n h i b i t o r s o f F i g u r e 1 p r e v e n t e d t h e f o r m a t i o n o f complex-type o l i g o s a c c h a r i d e s of the envelope g l y c o p r o t e i n s , but d i d not prevent t h e formation of f u l l y i n f e c t i o n s RSV-particles (11). In c o n t r a s t , formation o f i n f e c t i o u s MuLV was i n h i b i t e d by d e o x y n o j i r i m y c i n , an i n h i b i t o r of glucosidase I (10). S i n d b i s - v i r u s i n f e c t e d c e l l s p r e s e n t e d an i n t e r e s t i n g system to study the r o l e o f p r o c e s s i n g o f N - l i n k e d o l i g o s a c c h a r i d e s . The E l and E2 g l y c o p r o t e i n s o f S i n d b i s v i r u s e a c h c o n t a i n two g l y c o s y l a t i o n s i t e s ( 1 2 ) , and one g l y c o s y l a t i o n s i t e on E l and E2 c a r r i e s e x c l u s i v e l y complex-type o l i g o s a c c h a r i d e s when t h e v i r u s i s grown i n a v i a n o r mammalian c e l l s . H s i e h e t a l . (4) c o u l d show t h a t t h e f o l d i n g o f t h e p o l y p e p t i d e c h a i n s d e t e r m i n e d t h e extent of processing. I t i s shown i n T a b l e 1 t h a t when N - g l y c o s y l a t i o n i s i n h i b i t e d by t u n i c a m y c i n , t h e p r e c u r s o r p r o t e i n o f E2 (pE2) i s n o t c l e a v e d t o E2, t h e c e l l - s u r f a c e e x p r e s s i o n o f pE2 i s i n h i b i t e d , and v i r u s b u d d i n g d e c r e a s e s ( 1 3 ) . O t h e r work has shown t h a t c l e a v a g e o f pE2 t o E2 i s r e q u i r e d f o r v i r u s release (14). Allowing g l y c o s y l a t i o n t o occur, but p r e v e n t i n g g l u c o s e - t r i m m i n g by t h e g l u c o s i d a s e I - i n h i b i t o r s N-methyl d e o x y n o j i r i m y c i n o r c a s t a n o s p e r m i n e and t h u s e q u i p p i n g the v i r a l g l y c o p r o t e i n s with the o l i g o s a c c h a r i d e s Glc^Man^ ^GlcNAc , s t i l l p r e v e n t e d c l e a v a g e o f p E ( a n d hence v i r u s r e l e a s e ) , But a l l o w e d c e l l - s u r f a c e e x p r e s s i o n o f PE2 (15-16). The same r e s u l t was o b t a i n e d e a r l i e r w i t h bromoconduritol, t h a t caused equipping the v i r a l g l y c o p r o t e i n s w i t h GlcMan^ Q G 1 C N A C ( 1 7 ) . A l l o w i n g the removal o f the glucose group ( b u t p r e v e n t i n g mannose-trimming u s i n g deoxymannojirimycin), equipping the g l y c o p r o t e i n with Man^ g G l c N A c ^ - o l i g o s a c c h a r i d e s , p e r m i t t e d c l e a v a g e o f pE2 and allowed v i r u s budding (16). Thus, t h e p r e s e n c e o f a s i n g l e g l u c o s e group p e r o l i g o s a c c h a r i d e c h a i n d e t e r m i n e d whether o r n o t t h e p r o t e i n c a n be p r o t e o l y t i c a l l y c l e a v e d . These and o t h e r s t u d i e s (5) i n d i c a t e an e s s e n t i a l r o l e o f g l u c o s e t r i m m i n g i n t h e m a t u r a t i o n o f some v i r u s e s . 2

2

S i n d b i s v i r u s c u l t u r e d i n t h e presence o f t h e mannosidase-I



NUCLEOTCDE ANALOGUES

I —

-

F i g u r e 1. Processing of N-linked oligosaccharides. a b b r e v i a t i o n s , see T a b l e 1. •, GlcNAc; 0, Man; X, G l c ; ·, G a l ; •, NeuAc. DIM,1,4-dideoxy-1,4-imino-D-mannitol; 2,5-dihydroxymethYl-3,4-dihydroxYpyrrolidine

For


8.

DATEMAANDOLOFSSON



i n h i b i t o r d e o x y m a n n o j i r i m Y c i n buds p r e f e r e n t i a l l y from i n t e r n a l membranes, r a t h e r t h a n t h e c e l l - s u r f a c e membrane (16)· I n t h e presence o f the mannosidase-II i n h i b i t o r swainsonine (see F i g u r e 1) t h e r e l e a s e o f i n f e c t i o u s S i n d b i s v i r u s i s n o t d i f f e r e n t f r o m that of untreated c u l t u r e s . In f a c t , the maturation o f a l l e n v e l o p e d v i r u s e s s o f a r s t u d i e d seems n o t t o be a f f e c t e d by blocking oligosaccharide processing a t the l e v e l of the G o l g i enzymes N - a c e t y l g l u c o s a m i n y l t r a n s f e r a s e I o r mannosidase I I ( 5 ) . Y e t , many o l i g o s a c c h a r i d e s o f v i r a l g l y c o p r o t e i n s a r e p r o c e s s e d p a s t t h i s s t a g e t o form complex-type o l i g o s a c c h a r i d e s . What, t h e n , i s t h e b i o l o g i c a l r o l e o f t e r m i n a l g l y c o s y l a t i o n of v i r a l glycoproteins? Based on e v i d e n c e p r e s e n t e d e l s e w h e r e , we s u g g e s t e d ( 5 ) , t h a t t e r m i n a l g l y c o s y l a t i o n o f v i r a l g l y c o p r o t e i n s may p l a y a r o l e a t t h e v i r u s - h o s t l e v e l , f o r example i n v i r a l s p r e a d and p a t h o g e n e s i s . To s t u d y t h e s e phenomena i n t h e i n t a c t o r g a n i s m , i n h i b i t o r s a c t i v e o n l y i n v i r u s - i n f e c t e d c e l l s a r e needed. I n h i b i t i o n o f T e r m i n a l N- and O - G l y c o s y l a t i o n Herpesvirus-Infected C e l l s

Specific for

We c h o s e t o s t u d y t h e p o s s i b i l i t y o f development o f v i r u s - s p e c i f i c i n h i b i t o r s o f g l y c o s y l a t i o n i n t h e herpes simplex v i r u s (HSV) system, b e c a u s e HSV has been w i d e l y u s e d t o s t u d y mechanisms o f s p e c i f i c a n t i v i r a l a g e n t s ( 1 8 ) , and t h e p a t h o g e n e s i s o f HSV has been s t u d i e d i n s e v e r a l a n i m a l models (19) a l l o w i n g e v a l u a t i o n i n v i v o . The HSV-1 s p e c i f i e d g l y c o p r o t e i n gC-1 i s u s e d as a m o l e c u l a r p r o b e b e c a u s e t e r m i n a l g l y c o s y l a t i o n o f gC-1 may be i m p o r t a n t i n v i v o . Evidence f o r t h i s a r e : r e m o v a l o f t e r m i n a l s u g a r s from gC-1 changes t h e a n t i g e n i c i t y o f t h e p e p t i d e p a r t o f t h e m o l e c u l e ( 2 0 ) , and t h e C 3 b - r e c e p t o r a c t i v i t y o f gC-1 i s s i a l i d a s e - d e p e n d e n t ( 2 1 ) . F u r t h e r m o r e , gC-1 c o n t a i n s N- and 0 - l i n k e d o l i g o s a c c h a r i d e s , which c a n be s t u d i e d s e p a r a t e l y s i n c e t u n i c a m y c i n - t r e a t m e n t does not j e o p a r d i z e t h e p r o t e o l y t i c s t a b i l i t y o f gC-1 ( 2 2 ) . A l s o , e x p e r i m e n t a l t o o l s t o r a p i d l y p r o b e changes i n N- and 0 - l i n k e d o l i g o s a c c h a r i d e s o f gC-1 have been d e v e l o p e d (23-24). Terminal g l y c o s y l t r a n s f e r a s e s are located i n s i d e the t r a n s - G o l g i compartment as i s t h e a c c e p t o r g l y c o p r o t e i n (_1). However, t h e s u b s t r a t e s o f t h e t r a n s f e r a s e s , t h e s u g a r n u c l e o t i d e s a r e p r e s e n t i n t h e c y t o s o l . H i r s c h b e r g and co-workers (25) c o u l d show t h a t s u g a r n u c l e o t i d e t r a n s l o c a t o r p r o t e i n s i n t h e G o l g i membranes t r a n s p o r t s u g a r n u c l e o t i d e s i n t o t h e G o l g i compartment and t h i s t r a n s l o c a t i o n i s c o u p l e d t o e x p o r t o f t h e c o r r e s p o n d i n g n u c l e o s i d e 5 *-monophosphate, as shown f o r UDP-Gal i n F i g u r e 2. The t r a n s l o c a t i o n o f s u g a r n u c l e o t i d e s i n t o t h e G o l g i compartment c a n be i n h i b i t e d by n u c l e o s i d e 5 -monophosphates ( 2 6 ) , and t h i s phenomenon r e p r e s e n t s t h e t a r g e t f o r the design of v i r u s - s p e c i f i c g l y c o s y l a t i o n i n h i b i t o r s . The i n h i b i t i o n o f s u g a r n u c l e o t i d e t r a n s l o c a t i o n l i m i t s t h e amount o f t h e s u b s t r a t e f o r t h e g l y c o s y l t r a n s f e r a s e , and c a u s e s a b l o c k i n glycosylation. H e r p e s v i r u s s p e c i f i c i t y i s o b t a i n e d by s e l e c t i v e p h o s p h o r y l a t i o n o f a n u c l e o s i d e t o an i n h i b i t o r y n u c l e o s i d e 5'-monophosphate i n i n f e c t e d c e l l s . 1


120

N U C L E C m D E ANALOGUES


Table 1.

Role of G l y c o s y l a t i o n i n the Sindbis Virus/BHK C e l l System

Cleavage

Cell-surface expression Virus budding PE , E

Location of block

Inhibitor used

LLO assembly

TM

No

No

Decreased

Glc trimming

Be

No

Yes

Decreased

Glc trimming

dN, cas, MdN

No

Yes

Decreased

Man I trimming

dMM

Yes

Yes

Yes, but intracellularly

Man I I trimming

swa

Yes

Yes

Yes

P

V 2 E

2

2

Abbreviations: LLO, l i p i d - l i n k e d oligosaccharide; TM, tunicamycin; Be, bromoconduritol; dN, 1-deoxynojirimycin; cas, castanospermin; MdN, N-methyl-l-deoxynojirimYcin; dMM, l-deoxymannojirimYcin; swa, swainsonin. For references, see t e x t .

out in

Golgi vesicle Substrate + acceptor . UDP-Gal + HO-R

PORT: UDP-Gal i_

Galactosyl transferase ANTIPORT: UMP

UMP

UDP t Gal-O-P,

I I Figure

2.

J I

etc.

Schematic diagram of sugar n u c l e o t i d e

translocation.


8.


DATEMA AND OLOFSSON

We have s t u d i e d (24, 27) t h e f e a s i b i l i t y o f t h i s a p p r o a c h with the n u c l e o s i d e analog (E)-5-(2-bromovinyl)-2 -deoxyuridine (BVdU). BVdU i s a s e l e c t i v e anti-HSV-1 agent i n t e r f e r i n g w i t h v i r a l DNA s y n t h e s i s ( 1 8 ) . The s e l e c t i v i t y o f BVdU i s due i n p a r t t o i t s p h o s p h o r y l a t i o n by t h e HSV-induced t h y m i d i n e k i n a s e . In a d d i t i o n t o i n t e r f e r i n g w i t h v i r a l DNA s y n t h e s i s , t h e drug a f f e c t s t h e s y n t h e s i s o f v i r a l g l y c o p r o t e i n s (24, 28-29), an e f f e c t a l s o dependent on i n d u c t i o n o f t h e v i r a l t h y m i d i n e k i n a s e . The e f f e c t on g l y c o p r o t e i n s can be s t u d i e d s e p a r a t e l y from t h e e f f e c t on DNA s y n t h e s i s by a d d i n g t h e drug a f t e r t h e o n s e t o f v i r a l DNA s y n t h e s i s ( i . e . , 6 h p . i . ) . An a n a l y s i s o f the e f f e c t on g l y c o p r o t e i n gC-1 showed t h a t i n c o r p o r a t i o n o f g a l a c t o s e and s i a l i c a c i d i n t o N - l i n k e d o l i g o s a c c h a r i d e s and i n c o r p o r a t i o n o f s i a l i c a c i d , and t o a l e s s e r e x t e n t , o f g a l a c t o s e i n t o 0 - l i n k e d o l i g o s a c c h a r i d e s was b l o c k e d ( 2 7 ) . This r e s u l t e d i n formation of normal amounts o f gC-1, b u t w i t h d i f f e r e n t o l i g o s a c c h a r i d e s , i . e . , w i t h t e r m i n a l GlcNAc and Fuc i n N - l i n k e d o l i g o s a c c h a r i d e s and t e r m i n a l 0 - l i n k e d GalNAc.


f

T h i s i n h i b i t i o n o f t e r m i n a l g l y c o s y l a t i o n was not c a u s e d by i n h i b i t i o n o f f o r m a t i o n o f UDP-hexoses, i n h i b i t i o n o f i n t r a c e l l u l a r transport of glycoproteins i n a g a l a c t o s y l t r a n s f e r a s e - d e f i c i e n t c e l l l i n e , nor by i n h i b i t i o n o f a c c e p t o r glycoprotein synthesis. No e v i d e n c e f o r f o r m a t i o n o f a s u g a r n u c l e o t i d e a n a l o g o f BVdU was o b t a i n e d . The i n h i b i t i o n o f terminal g l y c o s y l a t i o n d i d require formation of BVdU-5 -monophosphate, and was t h e r e f o r e not o b s e r v e d i n c e l l s i n f e c t e d w i t h T K - n e g a t i v e v a r i a n t s o f HSV-1. The b l o c k d i d o c c u r a l s o i n HSV-2 i n f e c t e d c e l l s , which can p h o s p h o r y l a t e BVdU t o i t s 5'-monophosphate (BVdUMP), b u t not any f u r t h e r . In a c e l l - f r e e system BVdUMP i n h i b i t e d t h e t r a n s p o r t o f p y r i m i d i n e s u g a r n u c l e o t i d e s ( s u c h as UDP-Gal, CMP-NeuAc) a c r o s s G o l g i membranes and, as a consequence, i n h i b i t e d t h e t e r m i n a l g l y c o s y l a t i o n . No i n h i b i t i o n o f t r a n s l o c a t i o n o f p u r i n e sugar n u c l e o t i d e was o b s e r v e d , nor d i d BVdUMP i n h i b i t g a l a c t o s y l t r a n s f e r a s e . 1

Taken t o g e t h e r , t h e s e r e s u l t s (27) show t h a t i t s h o u l d be p o s s i b l e t o o b t a i n a n u c l e o s i d e s e l e c t i v e l y p h o s p h o r y l a t e d by HSV t h y m i d i n e k i n a s e t o a 5 -monophosphate which w i l l i n h i b i t s u g a r n u c l e o t i d e t r a n s l o c a t i o n , i n o t h e r words a v i r u s - s e l e c t i v e glycosylation inhibitor. F u r t h e r m o r e , i t s h o u l d be. p o s s i b l e t o obtain HSV-specific i n h i b i t o r s of f u c o s y l a t i o n or mannosylation by u s i n g g u a n o s i n e a n a l o g s s e l e c t i v e l y p h o s p h o r y l a t e d by HSV-coded t h y m i d i n e k i n a s e (17, 3 0 ) . 1

Implications With the e x c e p t i o n of c h r o n i c a d m i n i s t r a t i o n o f o r a l a c y c l o v i r , chemotherapy has not been i m p r e s s i v e l y u s e f u l i n t h e management o f r e c u r r e n t HSV i n f e c t i o n s (32)· U s i n g t h e r a p e u t i c regimens o f a c y c l o v i r , b u c i c l o v i r or foscarnet e f f e c t i v e l y blocking HSV-1 r e p l i c a t i o n and d i s e a s e development i n s y s t e m i c , c u t a n e o u s and c e n t r a l nervous s y s t e m - i n f e c t i o n i n m i c e , no c l i n i c a l b e n e f i t was o b t a i n e d when t h e v i r u s (HSV-1) i n f e c t e d t h e s k i n o f mice v i a sensory nerves ( i n z o s t e r i f o r m - s p r e a d models), d e s p i t e the p r e s e n c e o f immunity and d r u g a v a i l a b i l i t y ( 3 2 ) . Thus, i n t h e s e


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models o f r e c r u d e s c e n t d i s e a s e , as i n c l i n i c a l t r i a l s o f a c u t e t r e a t m e n t o f r e c u r r e n t HSV i n f e c t i o n s , t h e b e n e f i t s o f p o t e n t and s e l e c t i v e i n h i b i t o r s o f HSV r e p l i c a t i o n were m i n i m a l . This i m p l i e s t h a t management o f r e c u r r e n t H S V - i n f e c t i o n s r e q u i r e s an a p p r o a c h o t h e r t h a n i n h i b i t i n g HSV DNA s y n t h e s i s . Selective i n t e r f e r e n c e with v i r a l p r o t e i n g l y c o s y l a t i o n , r e s u l t i n g i n a l t e r e d immunogenicitγ o f t h e v i r a l g l y c o p r o t e i n s may be such an approach.

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1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Kornfeld, R.; Kornfeld, S. Annu. Rev. Biochem. 1985, 54, 631-64. Romero, P. Α.; Herscovics, A. Carbohydr. Res. 1986, 151, 21-28. Dunphy, W. G.; Rothman, J. E. Cell. 1985, 43, 13-21. Hsieh, P.; Rosner, M. R.; Robbins, P. W. J. Biol. Chem. 1983, 258, 2555-61. Datema, R.; Olofsson, S.; Romero, P. A. Pharmac. Ther. 1987, 33, 221-86. Roseman, S. In Biology and Chemistry of Eucaryotic Cell Surfaces; Lee, E. Y. C.; Smith, Ε. E., Eds.; Academic: New York, 1974; pp. 317-54. Schachter, H. Biol. Cell. 1984, 51, 133-46. Schwarz, R. T.; Datema, R. Trends Biochem. Sci. 1984, 9, 32-34. Schwarz, R. T.; Rohrschneider, J. M.; Schmidt, M. F. G. J. Virol. 1976, 12, 782-91. Pinter, Α.; Honnen, W. J.; L i , J. S. Virology. 1984, 136, 196-210. Bosch, J. V.; Schwarz, R. T. Virology. 1984, 132, 95-109. Strauss, E. G.; Strausse, J. H. In The Togavividae and Flaviviridae; Schlesinger, S.; Schlesinger, M. J., Eds.; Plenum Publishing Corp.: New York, 1986; pp. 35-90. Schlesinger, M. J. In Virology; Fields, Β. N.; Knipe, D. M.; Chancok, R. M.; Melnick, J. L.; Roizman, B.; Shope, R. E., Eds.; Raven Press: New York, 1985; pp. 1021-32. Garoff, J.; Kondor-Koch, C.; Riedel H. Curr. Top. Microbiol. Immunol. 1982, 99, 1-50. Schlesinger, S.; Koyama, A. H.; Malfer, C.; Gee, S. L.; Schlesinger, M. J. Virus Res. 1985, 2, 139-49. McDowell, W.; Romero, R. Α.; Datema, R.; Schwarz, R. T. Virology. 1987, 161, 37-44. Datema, R.; Romero, P. Α.; Rott, R.; Schwarz, R. T. Arch. Virol. 1984, 81, 25-39. De Clercq, E. Biochem. J. 1982, 2051, 1-13. Stanberry, L. R. Progr. Med. Virol. 1986, 33, 61-77. Sjöblom, I.; Lundström, M.; Sjögren-Jansson, E.; Glorisoso, J. C.; Jeansson, S.; Olofsson, S. J. Gen. Virol. 1987, 60, 545-54. Smiley, M. L.; Friedman, H. M. J. Virol. 1985, 55, 857-61. Svennerholm, B.; Olofsson, S.; Lundén, R.; Vahlne, Α.; Lycke, E. J. Gen. Virol. 1982, 63, 343-49.


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Lundström, M.; Olofsson, S.; Jeansson, S.; Lycke, Ε.; Datema, R.; Månsson, J.-E. Virology. 1987, 161, 385-94. Olofsson, S.; Lundström, M.; Datema, R. Virology. 1985, 147, 201-05. Hirschberg, C. B.; Snider, M. D. Annu-Rev. Biochem. 1987, 56, 63-88. Capasso, J. M.; Hirschberg, C. B. Biochim. Biophys. 1984, 777, 133-239. Olofsson, S.; Milla, M.; Hirschberg, C.; De Clercq, E.; Datema, R. Virology. 1988, 166, 440-450. Misra, V.; Nelson, R. C.; Babiuk, L. A. Antimicrob. Agents Chemother. 1983, 23, 857-65. Siegel, S. Α.; Otto, M. J.; De Clercq, E.; Prusoff, W. H. Antimicrob. Agents Chemother. 1984, 25, 566-70. Datema, R.; Ericson,A.-C.;Field, J . J., Larsson, Α.; Stenberg, K. Antiviral Res. 1987, 7, 303-16. Douglas, J. M.; Critchlow, C.; Benedetti, J.; Mertz, G. J.; Connor, J. D.; Hintz, Μ. Α.; Fahnlander, Α.; Remington, M.; Winter, C; Corey, L. New Engl. J. Med. 1984, 310, 1551-56. Kristofferson, Α.; Ericson,A.-C.;Sohl-Åkerlund, Α.; Datema, R. J . Gen. Virol. 1988, 69, 1157-66.

RECEIVED January 4, 1989


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